CA2243295A1 - Aromatic polycyclic retinoid-type derivatives, method for preparing same, and use thereof for making pharmaceutical and cosmetic compositions - Google Patents

Abstract

Novel aromatic polycyclic retinoid-type derivatives of general formula (I),wherein groupings R3 and R4 attached to the double bond between carbons 11 and 12 are cis groupings, and pharmaceutical and cosmetic compositions containing same, are disclosed.

Description

WO 97/26237 PCT ~ FR97 / 00079 TYPE AROMATIC POLYCYCLIC DERIVATIVES
R ~ TINOIDE THEIR PREPARATION PROCESS AND ~ EUR USE
FOR THE MANUFACTURE OF PHARMACEUTICAL COMPOSITIONS AND
. COSMETICS.
.. 5 The present invention relates to derivatives polycyclic aromatic retinoids of formula general:

17 ~ ~

15 ~ R3 C ~ CH3 ll 7 ~ R4 5 ~ 5 ~ 3 ~ 1 ~ 4 10 R7 R6 R5 (I) in which the R3 and R4 groups carried by the double bond between carbons 11 and 12 are in Ci5 and R1 ~ R2, R3, R4, Rs, R6, R7, X1, X2 and X3 have the meanings following:
l5 - R1 represents a hydrogen atom, a radical lower alkyl or a group of formula -CH2OH, -OH, -CHO, -COOH, -CORg, -CH2OCORg, -SH, -S-alkyl, -PO3H2, p-hydroxyphenylaminocarbonyl, tetrazol-5-ylaminocarbonyl, tetrazol-5-yl, 5-trifluoromethyl-tetrazoyl, and when this is possible their salts with tolerated acids physiologically, where R8 and Rg are:
. a hydrogen atom, an -OH group, a radical lower alkyl or a group of formula -OR1o, where R1o represents a branched or unbranched alkyl radical having from 1 to 20 carbon atoms, a branched or unbranched alkenyl radical having from 2 to 20 carbon atoms, an aryl or aralkyl radical, or . an amino group of formula:

CA 0224329 ~ 1998-07-13 WO 97/26237 PCT ~ FR97100079 - N ~
r, in which r and r ', identical or different, represent a hydrogen atom, an alkyl radical lower, an aryl or aralkyl radical, a residue of a-amino acid, a sugar residue or a heterocycle in which r and r 'taken together form a heterocycle.
- R2 represents a hydrogen atom, an atom halogen and more particularly a fluorine atom, a lower alkyl radical, a group of formula -COOH, -ORll, -SRll, - (CF2) nCF3 where n is an integer included 1 () between 0 and 10, or a group -OCOR11, and when this = is possible their salts with tolerated acids physiologically, or an amino group of formula:
~ r - N ~
r, in which r and r 'have the same meaning that previously, and R11 represents a hydrogen atom, a lower alkyl radical, a fluoroalkyl radical having from 1 to 6 carbon atoms and from 3 to 7 fluorine atoms, one aryl radical or an aralkyl radical.
- R3 represents a hydrogen atom, a radical ~ rifluoromethyl, an aryl radical, an aralkyl radical or '() a lower alkyl radical optionally substituted by a hydroxyl or by one or more fluorine atoms, by one lower alkoxy or by a group of formula - (C = O) R12, in which R12 represents a hydrogen atom, a lower alkyl radical, hydroxyl radical, radical ~ 5 lower alkoxy or an amino group of formula:
~ r - N ~
r, in which r and r 'have the same meaning than previously.
- R4 represents a hydrogen atom or a aryl radical.
- Rs represents a hydrogen atom, a radical lower alkyl, a halogen atom, a radical D CA 0224329 ~ 1998-07-13 fluoroalkyl having 1 to 6 carbon atoms and 3 to 7 fluorine atoms, or a group of formula -OR13 where R13 represents a hydrogen atom, an alkyl radical lower, an aryl radical or an aralkyl radical or a trifluoromethyl group.
- X1 is chosen from a carbon atom, a oxygen atom or sulfur atom, and then, - R6 and R7 are:
. methyl or ethyl radicals, in the case where X1 is a carbon atom, . nothing in the case where X1 is a sulfur atom or an oxygen atom, . one or two oxygen atoms in case X1 is a sulfur atom (case of a sul ~ oxide -SO- or a sulfone -S02-) - X2 and X3, identical or different, represent a carbon atom, an oxygen atom or a nitrogen atom, or X2-X3 are a single atom of sulfur, oxygen, or nitrogen, thus the nucleus carrying X2 and X3 can be benzene, pyridine, thiophenic, furanic, pyrrolic, or, in the case where X2 is an atom of oxygen and X3 a carbon atom, C13 and C14 represents a single carbon atom, thus the nucleus carrying X2 and X3 can be isoxazolic.
As pharmaceutically acceptable salts previous derivatives, there may be mentioned in a non-limitarive: salts of acetic and hydrochloric acids, cinnamic, citric, formic, hydrobromic, hydroiodic, hydrofluoric, malonic, methanesulfonic, oxalic, picric, maleic, lactic, nicotinic, phenylacetic, phosphoric, succinic, sul ~ uric, ~
tartaric, ammonium salts, piperazine, diethylamine, nicotinamide, urea, sodium, potass: ium, calcium, magnesium, zinc, lithium, methylamino, dimethylamino, trimethylamino, tris (hydroxymethyl) aminomethane.

MODIFIED

CA 0224329 ~ 1998-07-13 W 097/26237 PCTn ~ R97 / 00079 .

The term lower alkyl or alkoxy denotes groups of 1 to 6 linear or branched carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, butyloxy secondary.
All-trans retinoic acid, a metabolite of vitamin A has a large number of properties biological. Several molecules constructed from It) chemical modifications of this acid have been synthesized and have been shown to be biologically active. These analogs synthéti ~ ues and their derivatives are called retinoids, as defined by Sporn, MB and Roberts, AB, Ciba. Found. Symp., 113, 1-5, 1985 Among these the compounds, one can quote those described in the requests for European patent published under the numbers 350 846, 303 186, 253,302 in PCT international patent application published under number WO 93/11755, or in U.S. patents 5,300,522, 5,420,273, 4,578,498 and the ? () German patents 3602473 and 3715955, as well as in articles by Marcia I. Dawson et al. (J. Med Chem., 1989, 32, 1504-1517; J. Med. Chem. , 1993, 36, 26 ~ 5-2613).
Compounds which exhibit type activity retinoids are useful for treating mammals and more particularly of humans by chemoprevention and by chemotherapy, especially in the treatment of symptoms of many diseases such as dermatoses, acne, Darier's disease, psoriasis, ichthyosis, eczema. These compounds are also used for the ~ t) treatment and prevention of cancer diseases and many malignant hyperproli ~ erative diseases such as breast, prostate, lung, head cancer and neck, as well as certain types of original cancer epithelial and myelocytic leukemias. Compounds 3 ~ with retinoid-like activity are also useful for the treatment and prevention of atherosclerosis, IIt 3 ~ r ~ ~ h. ~ ~ T ~; ~

WO 97/26

2: ~ 7 PC ~ g7 / '00079 S

res ~ enosis from neointimal hyperproliferation, benign hyperproliferative pathologies such as endometrial hyperplasia, benign hypertrophy of the prostate, proliferative retinopathy, for treatment 5 autoimmune diseases and immunological disorders such as lupus erythematosus, for the treatment and prevention of diseases associated with lipid metabolism and for the treatment of the effects of the sun on the skin.
However, these retinoid-like compounds have significant side effects, including ~ severe irritation in the skin and mucous membranes, lipid toxicity, and are even teratogenic, making their delicate use in clinics (Kistler, A. et al. Arch Toxicol, 64: 616-622; ~ Retinoids in Oncology ", Edited by Waun Ki Hong & Reuben Lotan, The University of Texas MD
~ Anderson Cancer Center, Houston, Texas, USA, Marcel Dekker Inc, pages 127-146; ~ Retinoids in Clinical Practice ~, Edited by Gideon Koren The Motherisk Program, The Hospital for Sick Children and The University of Toronto, Toronto, '(1 Ontario, Canada, Marcel Dekker Inc.).
The adverse effects reported above have leads the Applicant to seek derivatives polycyclic aromatic retinoid active in the treatment and prevention of previous illnesses but ~ 5 with no side effects.
Surprisingly, the Applicant has evidence that the compounds of formula I in which R3 and R4 groups of the double bond between carbons 11 and 12 are of con ~ iguration cis have a higher activity than trans isomers corresponding or a mixture of cis / trans isomers, and may not have secondary effects in particular teratogens generally associated with the use of retinoid-like compounds. The prior art and in particular .5 the above mentioned patents and patent applications indicate logically the existence of cis and trans isomers due to CA 0224329 ~ 1998-07-13 the double bond between carbons 11 and 12, but are specifically interested in configuration compounds trans -ar this configuration is the one encountered in the reference arotinoid: acid (E) 4- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalenyl) -1-propenyl]
benzoïcue (TTNPB).
Still in accordance with the structure of the TTNPB, these compounds of the prior art are characterized by the presence of a substituent, more particularly of a methyl, on carbon 11 (R4 = -CH3 in ~ ormule I), while carbon 12 is not substituted (R3 = H in the formula I), whereas the compounds of the invention on the contrary, have a substituent, in particular a alkyl, at carbon 12 and not at carbon 11.
The research work carried out by the Applicant on the derivatives of general formula ~ I) of which the groups R3 and R4 are in cis, have led it to demonstrate that these compounds have activity ~ 0 intrinsic allowing them to modulate proliferation and cell differentiation, and authorizing their application in the treatment and chemoprevention of diseases such as breast cancer, breast cancer prostate, lung cancer, skin cancer and leukém: promyélocytaires ies in compositions not teratogenic.
The present invention therefore relates to polycyclic aromatic retinoid derivatives of ~ ormule general I defined above, their method of preparation as well as their use in human medicine and veterinary and in cosmetics.
Among the derivatives of formula (I), a series pré ~ éree is that in which R3 represents an alkyl lower or a trifluoromethyl radical where a group - (CH2) nCF3 where n is an integer between O and 10, and R4 represents a hydrogen atom.

WO 97126237 PCT ~ F ~ 97/00079 Another preferred series of derivatives of formula (1) se] on the invention are those in which R2 represents a hydrogen atom and R1 represents a tetrazoyl group or a COOH group. Among these, the series of derivatives for which R1 and R2 are different from a group -COOH
have properties - more particularly interesting; such derivatives are for example the compounds designated CB92834, CB77402, CB61692, CB63237 and CB39122 below. These derivatives are therefore distinguished 1 () clearly retinoid-type compounds derived from the TTNPB of prior art which relate to carbon 16 a group -COOH.
The invention envisages on a specifi ~ ue basis derivatives of formula (I) below:
l ~ Acid (z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8 -tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-5-carbo ~ lique, designated CB38416 and corresponding to the formula next :
HOOC ~

ll N
~ 3 ~ 1 Acid (E) 4- [1-trifluoromethyl-2- ~ 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-ethenyl]
benzoic, designated CB36493 and corresponding to the formula next :

W 097/26237 PCTnFR97 / 00079 HOOC ~

~ CF3 I

Acid (Z) 4- ~ 1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] benzoic, designated CB32706 and corresponding to the following formula:
HOOC ~

rl Acid (E) 4- [1-tri ~ luoromethyl-2- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -1-ethenyl]
henzqique, designated CB62899 and corresponding to the formula next :

~ CF3 ~ 1 ,.,><~
Acid (Z) 4- [1- (3 ', 4'-dihydro-4', 4 'dimethyl-1 ', 1'-dioxide-2'H ~ benzothiopyran-6'-yl) -2-propenyl] benzoic, designated CB72484 and meeting the following formula:

W 097 / 2623'7 PCT ~ R97 ~ 0079 HOOC ~

~ 1 o ~ S ~ o Le (Z) 5- [4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] phenyl] -1H-tetrazole, denotes CB92834 and corresponds to the following formula:
N ~ /
NOT
-~ ': ~ 5-- 1 Acid (E) 5- [4- [1-trifluoromethyl-2- (5,6,7,8-~ etrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-etheny ~] phenyl] -lH-tetrazole, designated CB77402 and corresponding has the following formula:
NOT /
NOT
H
~ ~ _ ,, CF3 1 () WO 97/26237 PCT ~ R97tO0079 Le (Z) 5- [4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] phenyl] -1H-tetrazole, designed CB61692 and corresponding to the following formula: -~ N - N
NOT
H
'''''I' . ~ Acid (E ~ 5- [4- [1-trifluoromethyl-2- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -1-ethenyl] phenyl] -1H-tetrazole, designated CB63237 and corresponding to the following formula:

I ~) Le (Z) 5- [4- [1- (3 ', 4'-dihydro-4', 4'-dimethyl-1 ', 1'-dioxide-2'H-1'-benzothiopyran-6'-yl) -2-propenyl]
phenyl] -lH-tetrazole, designated CB39122 and corresponding to the following formula:

WO 97n62.37 PCT ~ FR97 / 00079 -NOT
~ r I

0 ~ ~ 0 Acid (Z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] thienyl-5-carboxylic, designated CB30382 and corresponding to the formula next :
tlOOC ~, Le (Z) 5- ~ 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetram ~ thyl-2-naphthalenyl) -2-propenyl)] 5-thienyl] - 1H
tetrazole, designated CB92855 and corresponding to the formula I n following:

'NOT
X- ~
X ~
Acid (Z) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-carbo ~ yli ~ eu, designated CB16279 and corresponding to the formula 1 ~ following:

WO 97/26237 PCTA ~ R97 / 00079 HOOC ~

Acid ~ Z) 2- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-5-carboxylic, designated CB90525 and corresponding to the formula next :
HOOC ~

Acid (Z) 5- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-carboxyli ~ eu, designated CB56004 and corresponding to the formula 1 ~ next:
HOOC
N ~

Acid (Z) 5- [1- (5,6,7,8 tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] isoxazole-3-carboxylic, designated CB73069 and corresponding to the formula next :

W 097126237 PCT ~ FR97 / ~ 0079 .

HOOC

N ~

Acid (Z) 5- [1- ~ 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl)] isoxazole-3-carboxylic, designated CB54647 and corresponding to the formula . ~ next:
HOOC ~
N ~

Le (Z) 1- [4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] phenyl ~ -5-tri ~ luoromethyl-1H-tetrazole, designated CB29830 and corresponding 1 () to the following formula:
N ~ 3 NOT
~ 3 The invention also relates to the preparation of derivatives of formula (I) and the use thereof l ~ for the treatment and prevention of cancers of the type solid tumors, such as breast, lung, prostate or liver, as well as for the treatment and prevention of skin diseases, such as psoriasis W 097/26237 PCT ~ FR97 / 00079 e ~ acne. The invention also relates to the compositions pharmaceutical or cosmetic containing as a principle active at least one derivative of formula (I).
The derivatives of formula (I) and their isomers of trans configuration can be obtained according to the method known to Wittig by condensing a compound of formula:

~ PPh3 Br with a compound of formula:

o ~ X3 ~

R ~ R1 I () in the ~ uelles. R1, R2, R3, R4, Rs, R6, R7, x1, X2 and X3 have the same meaning as in formula (I).
. The derivatives of ~ ormule (I) can be prepared by any other method known to those skilled in the art, such as that dehydration of an alcohol corresponding to one or other of the following formulas:
Rl X3 ~ Rl X3 ~
R2 ~ lx2 R2 ~ lx2 R3 ~ 3 ~ OH

> ~ ~ ~ ~ 4 WO 97126237 PCT ~ R97 / 00079 .

in which R1, R2, R3, R4, Rs, R6, R7, X1, X2 and X3 have the same. ~ ignification ~ eu in formula (I).
It can also be a method of the type Horner-Emmons consisting of condensing a carbonyl compound (aldehyde or ketone) of ~ ormule:

~ O

with a phosphonate of formula:
EtO R3 Eto _ p ~ X3 ~

~ R

in which R1, R2, R3, R4, Rs, R6, R7, Xl, X2 and X3 I () has ~ the same meaning as in the formula ~ I) The cis and trans isomeric forms of the derivatives get ~ s by these different methods can be separated and purified either during the synthesis process by change of solvent or addition of salt (March, J., Modern 1 ~ Organic Synthesis, 3rd Edition, Wiley Interscience, p. 845-854), either at the final stage, according to known techniques, such as, for example, recrystallization, HPLC
preparative or chromatography.
In addition, it is possible from derivatives of 2 ~ formul ~ (I) and their trans isomers obtained according to previous methods, to prepare other derivatives by classic reactions at the level of one or more of ~ radicals Rl, R2, R3, R4, Rs, R6, R7, X1, X2 and X3. We can cite for example the following reactions:
A carboxylic acid ester of formula (I) in which R1 is a group -COOR1o, can be saponified CA 0224329 ~ 1998-07-13 W 097/26237 PCT ~ FR97 / 00079 by known methods, for example by treatment with alkaline solutions, especially by treatment with a hydro-alcoholic solution of sodium hydroxide or potassium at temperatures between ambient at the boiling point of the reaction mixture. Acid carboxylic thus obtained can be transformed into amide via ~ assage by an acid halide or transformed into an amide directly using a coupling reaction ~ eptidic, for example using as an agent 1 () coupling of carbonyldiimidazole (CDI) and as an amine 5-aminotetrazole in solution in TH ~ at temperature ambient (Paul R., Anderson GW, J. Am. Chem. Soc., 82, 4596, 1960).
- A carboxylic acid of formula (I) in l ~ which R1 is a -COOH group, can be converted by a known method, for example by treatment with chloride of thionyl, in toluene or pyridine, or by phosphorus trichloride or pentachloride in toluene, in acid chloride. This acid chloride can be ~ t) converted to an ester by reaction ~ with an alcohol, or to an amide corresponding by reaction with an amine.
- A carboxylic acid or an acid ester carboxylic of formula (I) in which R1 is a group -CQOH or a group -COOR1o, can be reduced by known methods to give the corresponding alcohol where R1 is a group -CH2OH-- A sulfide of formula (I), or its isomer trans, in which X1 is a sulfur atom ~ -S-), can be oxidized to sulfoxide (-SO-) or sulfone SO2-), R6 and R7 are then identical or different and represent either nothing (case of a sulfide: -S-), or a oxygen (case of a sulfoxide: -SO-) or two oxygen (case d ~ a sulfone: -SO2-). Oxidation of a sulfide group can be performed using oxidizing agents such as than periodates (e.g. sodium periodate) or using organic peracids such as m- acid CA 0224329 ~ 1998-07-13 W 09712 ~ 237 P ~ T ~ F ~ 97 ~ aO79 .

chloroperbenzoic acid (mCPBA). When oxidation is carried out using an organic peracid, about 1 equivalent allows to obtain a sulfoxide whereas the use of 2 peracid equivalents lead to sulfone - An amide of formula (I) in which R1 is a -CONrr 'group, can be reduced by known methods so as to give an aldehyde (R1 = -CHO), for example by diisobutylaluminum hydride in solution in the toluene, preferably using THF as the solvent 1 () reaction at temperatures between - 78 ~ C and the ambient - An aldehyde of formula (I) in which R1 is a -CHO group, can be oxidized by known methods of way, - to give a carboxylic acid (R1 = -COOH) or a 1 ~ carboxylic acid ester (R1 = -COOR1o), for example by Corey's method (Corey EJ et al., J. Am. Chem. Soc., 30, 5616, 1968) involving manganese dioxide, sodium cyanide, acetic acid and methanol to room temperature.
'() - A nitrile derivative of ~ ormule (I) in which Rl is a -CM group, can be hydrolyzed to acid carboxylic (R1 = -COOH) corresponding by known methods, for example by treatment with alkaline bases, more particularly by treatment with a hydro-alcoholic solution of hydroxide sodium or potassium at temperatures between the ambient and the boiling point of reaction mixture.
- A nitrile derivative of ~ ormule (I) in which ~ () Rl is a -CN group, can be trans ~ orm in lH-tetrazole by known methods, for example by treatment with trimethylsilane azide N3SiMe3 in the presence or not catalyst such as dibutyltin oxide (Bu) 2SnO
in aromatic solvents pre ~ erably toluene or benzene at temperatures between ambient and the boiling point of the reaction mixture.

CA 0224329 ~ 1998-07-13 WO 97126237 PCTA ~ R97 / 00 ~ 79 - A brominated, iodized or chlorinated aromatic derivative of Formula (I) in which R1 is a bromine, iodine atom or chlorine, can be transformed by known methods nitrile derivative (Rl = -CN), for example by the reaction . ~ by Rosenmund-von Braun using copper cyanide in a solvent, preferably dimethylformamide or quinoline at temperatures between ambient and the boiling point of the reaction mixture.
- A brominated, iodized or chlorinated aromatic derivative of 1 () formula (I) in which R1 is a bromine, iodine atom or chlorine, can be transformed by known methods of carboxylic acid (R1 = -COOH), for example by halogen-metal exchange using butyllithium (primary, secondary or = tertiary) in solution in cold THF (-78 ~ C to 0 ~ C) and carbon dioxide condensation and then rise to the ambient.
- A brominated, iodized or chlorine aromatic derivative of formula (I) in which R1 is a bromine atom, ~ iodine ~ 0 or chlorine, can be transformed by known methods in carboxylic acid ester (R1 = -COOR), for example by halogen-metal exchange using butyllithium (primary, secondary or tertiary) in solution in THF
cold (-78 ~ C to 0 ~ C) and condensation on a chloroformate alkyl.
- The derivatives of formula (I) in which R1 is a -COOH or -tetrazoyl group, can be transformed by known methods of salts with bases physiologically acceptable, non-toxic, inorganic or organic, for example in alkali metal salts or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, as well only salts with ammonia ~ eu or non-amines toxic.
~ 5 - A carboxylic acid of formula (I) in which R1 is a group -COOH, can be converted by a WO 97/26237 PCTnFR97 / 00079 known method, for example by a type rearrangement Curtius, with diphenylphosphorane azide in presence of triethylamine in toluene at 80 ~ C, followed d ~ an addition of an alcohol of the ROH type, preferably f ~ methyl alcohol (R = Me) or ~ enzymatic (R = benzyl), carbamate -NHCOOR, which by treatment with sodium hydroxide 10% aqueous (R = Me) or by hydrogenation (R = benzyl) leads to an aniline of formula (I) where R1 is a group I () - An aniline of formula (I) in ~ uelle Rl is a group -NH2, can be converted by methods known trifluoroacetylation, for example using 2- (~ rifluoroacetyloxy) pyridine (TFA ~) in ether at temperatures between 0 ~ C at the boiling point of the reaction mixture (~. Keumi et al., Bull Chem. Soc Jpn., 63, 2252, 1990), in the trifluoromethylated amide of formula (I) where R1 is a group -NH (C = O) CF3. Amide trifluoromethylated of formula (I) can be converted by known methods in chlorinated imine, pre ~ erentially in ~ () using triphenylphosphine and tetrachloride carbon (K. Tamura et al. J. Org. Chem., 58, 32, 1993), to lead to the compound of formula (I) where R1 is a group -N = C (C ~ 3) (Cl) - A trifluoroacetimidoyl chloride of formula 2 ~ (I) where R1 is a group -N = C (CF3) (Cl) can be cyclized by known methods, preferably by azide sodium in acetic acid at 70 ~ C (D. Armor et al., Bioorg. & Med. Chem. Lett., 6, 1015, 1996), to lead to a tetrazole of formula (I) where R1 is a group of formula ~ () following: e:
~ 3 -NOT
'N = N

- A halogenated compound of formula (I) where R1 is a bromine, chlorine or iodine can be converted by reaction CA 0224329 ~ 1998-07-13 WO 97/26237 PCT ~ FR97 / 00079 .

d ~ Arbuzov, preferably by treatment of diethylphosphite in toluene at the boiling point of reaction mixture, in diethyl phosphonate of formula (I) where R1 is a group -P (O) (OEt) 2.
- A p ~ osphonate of formula (I) where R1 is a group -P (O) (OEt) 2 can be hydrolyzed by methods known, for example in the presence of iodide of ~ rimethylsilyl, to lead to a phosphonic acid of formula (I) where R1 is a group -PO3H2.
I () The derivatives of formula (I) have very interesting properties on differentiation and cell proliferation, allowing to consider ~ eur use for therapeutic, dermatological and cosmetics. Among the therapeutic uses, one can 1 ~ cite the treatment and prevention of cancers of the type solidest tumors such as breast cancer, lung cancer, prostate or liver, as well as treatment and prevention of skin diseases, such as psoriasis and acne ~ () In addition, molecular biology work, reported below, helped define the profiles of activity of the compounds of the invention on the receptors retinoic and certain transcriptional factors However, it has recently been proposed to use RXR agonist compounds in the treatment of diabetes ~ on-insulin-dependent, inflammatory diseases and immune. Consequently, the compounds of the invention are useful for the treatment of non-insulin-dependent diabetes dependent, inflammatory and immune diseases.
~ 0 The invention therefore also relates to the use of derivatives of ~ ormule (I) for the manufacture of compositions pharmaceuticals useful in treatment or prevention cancers iansi only for the treatment of diabetes not insulin-dependent, anti-inflammatory diseases and

3 immune systems. They can also be used for CA 0224329 ~ 1998-07-13 WO 9 ~ 1 ~ 623 ~! PCT / F ~ 97 ~ Wa79 manufacture of cosmetic compositions useful in the treatment or prevention of skin diseases.
As a medicine, derivatives of the invention are administered in the form of a composition 5 pharmaceutical comprising at least said derivatives, under free form or in ~ form of a pharmaceutically salt acceptable, in combination with a vehicle or thinner traditional. Such compositions, which also part of the invention, may arise for enteral administration, for example in the form tablets, or for parenteral administration, for example under ~ elm solutions or suspensions intravenous or muscular injection, or for administration as a nasal spray.
As a cosmetic, derivatives of The invention are administered in the form of a composition cosmetic comprising at least said derivatives, in the form free or in ~ form of a pharmaceutically acceptable salt, in combination with a traditional vehicle or thinner. Of such compositions, which ~ are also part of can be presented for administration by enteral, for example in tablet form, or for parenteral administration, for example under form of solutions or suspensions injectable by route intravenous or muscular, or for administration in the form of a nasal spray, or advantageously for a ~ opic application, in ~ form of creams, ointments, milks, powders or gels.
Vehicles and thinners likely to be used in combination with the derivatives of the invention are those generally used in this type of indication.
For the previous indications, the dose depends the desired mode of administration and treatment. We obtains satisfactory results when the derivative is administered at a daily dose of 0.1 mg / kg and about 100 mg / kg. In humans, administration is CA 0224329 ~ 1998-07-13 WO 97/26237 PCT ~ R97 / 00079 2 ~
.

done for example intravenously, in one dose single per day or in divided doses up to several times a day, in the form of do ~ its units containing a concentration from 0.001% to about 0.01% of substance . ~ active.

I - Activity of derivatives of formula (I) on the cell proliferation.

A) MTT and SAMBA tests.
The activity of these derivatives on proliferation cell was assessed using the MTT test developed by T. Mosman (J. Immunol. Method., 65, 55-63, 1983). This test is currently used at NCI (National Cancer the Institute) as part of the screening program for anticancer molecules (Alley MC et al. Cancer Res., 48, 489-601, 1988). In addition, many laboratories specialized in research on chemotherapy and radiotherapy also use this model (Arnould R.
et al. Anticancer Res, 10, 145-154, 1990; Campling BG
Leuk Res., 12, 823-831, 1988; Kasugai S. et al. Japan Pharmacol, 52, 95-100, 1990; Price P. et al. Cancer Res., 50, 1392-1396, 1990).
The molecules ~ ui were the most ~ 5 interesting on the MTT test were evaluated on a test image analysis called SAMBA. Indeed the recent advances in image analysis have enabled new approaches to assessing different parameters of cell kinetics and measurement of 3 () distribution of chromatin. The data thus obtained are processed by different statistical tests.
Use of the System ~ 'Analyzes Automatic Scanning Microscopies 2005 (SAMBA 2005, Alcatel TITN, France) measures the influence of 3 ~ compounds studied at three levels:
- cell proliferation, W 097126 ~ 37 PCT ~ FR97 ~ oO079 .

- cell kinetics, - the distribution and texture of the chromatin.
These changes are representative of the influence of the test compound on the dif ~ erenciation cellular.

1 - Reactions, culture media and strains cellular.
The original molecules and the so-called products of 1 () reference tested were synthesized according to the procedures described previously or according to known methods of the skilled person. ~
Retino acid ~ that all-trans designated CB16178 and the 13-cis-retinoic acid designated CB81808 have been acquired 1 ~ with the company Sigma (Saint Quentin Fallavier, France).
Several reference products have been selected:
a) The natural liaands of the two classes of RAR and RXR nuclear receptors known to man from ~ () the axt:
. the all-trans retinoic acid designated CB16178.
. 9-cis retinoic acid prepared according to the Corey's method (Corey EJ, Gilman NW and Ganem BE, J. Am. Chem. Soc., 90, 5616, 1968), designated CB13407 and a ~ S of their isomers, . 13-cis retinoic acid designated CB81808.
b) Three reference retinoids known from the skilled person:
. TTNPB (Loeliger P. et al. Eur. J. Med Chem., 15, 9-15, 198Q) designated CB01570, . LGD1069 also designated CB32934 and LGD-CB14499 (Boehm MF et al., J. Med.Chem., 37, 2930-2941, 1994) -The cells cultured come from ATCC (American Type Culture Collection). From tumor cell lines tested, only results CA 0224329 ~ 1998-07-13 W 097t26237 PCT ~ R97 / 00079 .

obtained with four of them are presented below below:
- A549 (ATCC code: CCL 185) and A-427 (ATCC code : HTB 53) are lung cancer cells human.
- ZR-75-1 (ATCC code: CRL 1500 ~ and T47D (code ATCC: HTB 133) are breast cancer cells human.
The cell lines are maintained in 1 () monolayer culture at 37 ~ C in culture dishes closed (Nunc, Gibco BRL, Life Technologies, ~ Belgium) containing minimum essential medium (MEM, Gibco) supplemented with 5% fetal calf serum (FCS, Gibco), 0.6 mg / ml glutamine (Gibco) and a mixture of 200 IU / ml 1 ~ penicillin (Gibco), 200 ~ g / ml streptomycin (Gibco) and 0.1 mg / ml gentamycin (Gibco). Calf serum:
fetal is decomplemented for 1 hour at ~ 6 ~ C.

2 - Experimental otocoles.
~ na) MTT test.
The MTT test is carried out according to the method of Carmichael J. et al., Cancer Res., 47, 936-942, 1987 with certain modifications (Etievant C., Anticancer Res., 11, 305-312, 1991).
This test is based on mitochondrial reduction by ~ metabolically active living cells of MTT
(3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl bromide tetrazolium) yellowish in color product blue, formazan. The amount of formazan obtained is directly proportional to the number of living cells.
After incubating the cells for 24 hours in 96-well flat-bottom microplates, culture medium is replaced by 100 ~ l of fresh culture medium containing the drug to be tested. After 72 hours of incubation . ~ in the presence or absence of the molecule to be studied, the medium of culture is then replaced by 100 ~ l of MTT (Sigma, WO 9712623'1 PCT / FR97 / 00079 selgic) dissolved at a rate of 1 mg / ml in RPMI 1640 (Roswell Park Memorial Institute, Gibco).
The microplates are then incubated for 3 h at 37 ~ C and centered for 10 min at 400 g (GPR
S centrifugal, Beckman). MTT solution is replaced by 10 ~ l dimethyl sulfoxide (Merck). The microplates are shaken (Vari-Shaker, Dynatech) for 10 minutes. The optical density measurement is then performed (Reader DIAS, Dynatech) at a wavelength of 570 nm and at the 1 () reference wave length (maximum noise absorbance background) of 630 nm (Alley MC et al., Cancer Res., 48, 489-601, 1988).
In these micropla ~ ues, the control cells as the treated cells were incubated in a medium without the compounds to be tested for 24 hours. Cells controls are incubated in a drug-free environment for all the experimentation, while the treated cells are ncubated in different environments. These backgrounds contain the molecule to be tested in di ~ erent ~ () concentrations: 10 M, 10 M and 10 M. All tests are made in 6 duplicates.
Anal ~ its statistics:
The results are presented in ~ form of mean + standard error over mean (ESM). The c ~ m statistical comparisons are made according to the test Fisher: NS * = P <0.05; ** = P <0.01 *** P '- O, 001.
b) SAMBA test.
~ () Exponentially growing cells are cultured on glass slides (Kiss R. et al.
Eur. J. Cancer 27, 1268-1274, 1991) at the rate of 20 x 10 M to 60 x 10 M cells / ml ~ depending on the line cell considered) in at least 3 ml of medium ~ 5 essential (MEM, Gibco). The 18 x 18 mm slats are placed in 35 x 10 mm Petri dishes CA 0224329 ~ 1998-07-13 WO 97/26237 PCTA ~ R97 / 00079 (Becton-Dickison) The cells are thus cultivated for 96 h. The processing of cells, if it takes place, is 24 h after transplanting. -The culture medium is then replaced by environments comprising different concentrations of substances to be studied.
Control cells are grown in the absence of drugs.
For each experimental condition, 3 strips are ~ ixed after 96 h of culture in the EFA (75 I () volumes of ethanol 96 ~, 20 volumes of 40% neutral formalin and 5 volumes of pure acetic acid) for 20 min. Cells controls are ~ ixed at the same time. After fixing, the glass slides are mounted on histolosic slides using Canada balsam (DPX, 3DH Chemicals) and 1 stored at 4 ~ C in the dark.
The blades supporting the slats are then stained by the reaction of Feulgen R. (Z. Physiol. Chem., 135, 203-248, 1924) according to the protocol described by Kiss R.
et al (Modern. Pathol. 5, 655-660, 1992). All blades ~ () of a given experimental condition are colored at the same ~ emps for 1 h in the Feulgen reagent (pararosalinin Chloride-CI, Aldrich, France; Noritt PN5, BDH) after hydrolysis in HCl for 1 h at 22-24 ~ C The cells are kept at room temperature before analysis.
The advantage of Feulgen's coloring lies in the ability to stain specific ~ acon DNA and stoichiometric (Giroud F., Cell, 44, 177-188, 1982; Kiss .. et al., J. Histochem. Cytochem., 41, 6, 935-945, 1993).
~ () For each experimental condition, 900 nuclei are analyzed by the image analyzer. Each nucleus is characterized by 15 morphonuclear parameters of which 1 is of morphometric type, 5 of densitometric type and 9 of textural type (Brugal G. et al., J. Histochem. Cytochem., 27, 144-52, 1979; Pauwels O. and Kiss R., Meth. Find. Exp Clin. Pharmacol., 15, 113-124, 1993).

WO 9712623'1 PCTIFR97 / aaO79 .

These 15 parameters are calculated by software specific, from:
- Histograms of density values optical - Matrices of section lengths (Calloway M M., Comput. Graph. I ~ Proc Age, 4, 172-179, 1975).
- Co-occurrence matrices (Haralick RM and al., IEE Trans. Syst. Man Cybern. SMC -3, 610-620, 1973).
I () Statistioues and mathematical analysis:
Cell growth measurements and morphonuclear characteristics are presented under form of mean ~ standard error on the mean: ESM).
The comparison of the means is carried out using the F test Fisher's l ~ for probabilities of p <0.5 p <0.0 and p <0.001.
A principal component analysis followed by a canonical transformation is used to distinguish the nucleus ~ "typical" of the nuclei treated by drugs to ~ f) test These analyzes use multivariate analysis described by sartels PH (Anal. Quant. Cytol., 11, 433-439, 1980).
3 - Results.
a) Test ~ TT.
The results are reported in Tables 1 to 6 presented below. Average optical density measured for each experimental condition is expressed in percentage with respect to the control condition set equal ~ f) to 100 ~.
Table 1 below reports the results of the structure / activity study of compounds responding to the following general formula, on lines ZR-75-1 and T-47D:

CA 0224329 ~ l998-07-l3 W 097/26237 PCTn ~ R97 / 00079 .

~ R1 Table 1 X1R7R6 R5 R4 R3 R1 10-4M lo-6M lo-8M 10-4M 10-6M 10 8M
TTNPB C (Me) 2 H Me H COOH 15.7 69.8 60.6 3.5 61.7 58.5 CB0157A (4.4) (14.9) (18.2) (0.4) (1.3) (0.9) C ~ 777 ~ 7 N / A ~ OMe Me H COOH 93.5 112.8 113.5 86.3 120.2 129.1 (5.6) (7) (7.7) (9.1) (4.1) CB65757 SO2 OHeptyl Me H COOH 1,117.6 116.3 0 126.1 124.1 (1.6) (7.3) (6.7) (0) (3.6) (1.4) CB718n ~ C (Me) 2 Me HMe COOH 7.8 96 101,314.3113.2 131.7 (0.3) (3.3 ~ (1.8) (1.7) (6.3) (5.5) CB12994 SH HMe COOH31.8125.9121.41.851.8 67.6 (2.8) (1.5) (1.6) (0.4) (1) (2.4) CB39356 SO2 H HMe COOH59.6148.4 13336.4107.6 86 (2.6) (0.9) (2.6) (0.5) (1.8) (4.3) C'B7336 ~ C (Me) 2 HH Me CONH- 0 101,1119.2 0 53 62 tetra (0 ~ (1.7) (0.9) (0) (1.2) (2.2) zoyl CB6 ~ 5 ~ C '(Me) ~ H HMe tetra3,2102,4115,7Z, 8109.5 116.6 zoyl (1.6) (5.5) (6) (1.5) (4.8) (3.4) CB40 / ~ 7 .C (Me) 7 Me H Me tetra 0 107,4111.1 0 85.2 106 zoyl (~) (2) (1.7) (o) (2.8) (3.4) CB15068 SO ~ HH Metetra 59,399,999.2 32.2 87.8 100.6 zoyl (1.3) (1) (1.1) (1.7) (9.3) (0.8) S The level of proli ~ eration obtained for each line and for each product is expressed as a percentage compared to the controlled condition (100% + maximum, 6%
standard error on the mean).

I0 Table 2 below reports the results of the structure / activity study of compounds meeting the following general formula, on lines ZR-75-1 and T-47D:

CA 0224329 ~ l998-07-l3 W 097/26237 PCT ~ FR97 / 00079 _ 29 Rl ~ R3 ~ 4 X ~ Rs 47D: R7 R6 Table ~
ZR-75-1 ¦ T-47D
~! R7R6 X2 R5 R4 R3 Rl 10-4M 10-6M 10-8M 10-4M 10-6M 10-8M
CB28628 ~ (Me) 2 CH. HH Me COO ~ 19.4 83.5 80.8 4 59.3 93.2 (2.9) (19.8) (19.6) (0.6) (1.5) (2.4) CB3 ~ 416 C (Me) 2 MHH Me COOH 55.8 98.3 121.8 42.5 82.6 118.8 ~ 0.8) (1.9) (4.2) (1.6) (2.5) (4.7) CB3649 ~ 1 ~) 2CH HH CF3 COOH 8.6108.9 108 21.4 116.5 133.8 (1.3) (4.3) (4.4) (1.7) (7) (6.6) CB32705 ~ (Me) 2 CH Me H Me COOH0.793.1 95 0 88.6 94 (0.2) (5.5) (2.3) (0) (3) (3.6) CB62899 C (Me), CH Me H CF3 COOH 0.4 111.9 112.1 1.7 73.7 128.1 (l, 9) (6) (8.5) (1.5) (7.4) (3.5) CB41665 S CH HH Me COOH 48.5114.7 112 28 69.5 88.7 (3.1) (2.1) (1.8) (1) (2) (3.5) CB724 & 4 SO ~ CH HH Me COOH 128.8 137.6 144.6 99 128.5 129 (3) (2.8) (3.4) (2.5) (2.9) (4.1 CB9 ~ 34 C (Me ~ 2 CH HH Me Tetra 18.7 39.9 27.9 3.5 83.2 86.5 ~ zoyl (2.7) (12.6) (2.9) (0.5) (1.3) (2.7) CB77402 C (M ~! 2 CH HH CF3 Tetra 7.5 96.6 99.9 15.4 118 127.5 zoyl (0.3) (3.9) (3.5) (1.6) (4.3) (5.9) CB61652 ~ Me) 2 CHMe H Me Tetra 0 89.5 93.2 0 93.8 106.4 zoyl (0) (2.9) (1.5) (0) (2) (1.6) CB63237 C (Me) 2 CHMe HC ~ 3 Tetra 0 106.3 86.5 4.1 125.3 120.4 zoyl (0) (4.6) (2.8) (1.3) (5.6) (4.4) CB39122 SO ~ CH HH Me Tetra 74.2 97.3 101.6 57.1 100 102.5 zoyl (1.3) (3.1) (0.6) (2.5) (3.1) (0.9) The level of proliferation obtained for each S line and for each product is expressed as a percentage compared to the control condition (100% + maximum, 6%
standard error on the mean).
Table 3 below reports the results of the structure / activity study of compounds responding to the following general form, on lines ZR-75-1 and T-47D:

CA 02243295 l998-07-l3 WO 97/26237 PCTn ~ R97 / 00079 Table 3 Z ~ -75-1 T-47D

LGD- O COOH 42.4 104.5 106.7 1.3 82.7 88.2 CBl4499 (0.6) (1.4) (1.2) (0.6) (3.8) (32.2) LGDl069 CH2COOH 0 152.6 139.4 3.3 99.3 108 CB3 ~ 934 (o ~ (1) (2.5) (0.7) (2.8) (2.6) CB81516 OCONH (40H-Ph) 0 133.5 135.7 1.4 96.7 103.1 (0) (5.2) (4) (0.5) (2.5) (3.1) CB65801 CH2CONH (40H-Ph) 0.293.4 138.3 1.6 62.7 92.8 (0.2) (3.3) (3.1) (0.7) (3.1) (2.8) The level of proliferation obtained for each line and for each product is expressed as a percentage relative to the control condition (100% ~ maximum, 6%
standard error on the mean).
Table 4 below shows the results of the structure / activity study of compounds meeting the the following general formula, on the lines ZR-75-1 and T-47D:, O
~ l ~ y HE

Table 4 Connection Y Connection Name 10-4M 10-6M 10 8M 10-4M 10-6M 10-8M

CBl617 & trans trans OH all-7.3 57.2 46.9 1.8 52.6 77.2 trans- (0.8) (11) (11.7) (0.6) (1.4) (1.4) RA
CB81808 trans cis OH 13- 2.3 55 41.6 9.94 51.8 70.3 cis-RA (1.4) ~ 18.9) (9.5) (0.4) (1.9) (1.8) CB13407 cis trans OH9- 39.2 1 ~ 0.1 137 16.3 91.7 122 cis-RA (1,8) (1,4) (2) (1,4) (1,9) (2,7) CB05764 trans trans 4-amino 4-HPR 0.681.9 97.3 0 66.4 82.5 phenol (0.1) (2.3) (2.5) (0) (1.4) (5.1) CA 02243295 l998-07-l3 WO 9712623, 'PCTJF ~ 97 ~ 00079 The level of proli ~ eration obtained for each line and for each product is expressed as a percentage compared to the control condition (100% + maximum, 6%
standard error on the mean).
. ~ Table 5 below reports the results of the structure / activity study of compounds responding to the following general formula, on lines A549 and A-427:

Table 5 1 () A549 ¦ A-427 XlR7R5 R5 R4R3 Rl 10-4M 10-6M 10-3M 10-4M 10-6M 10-3M
CB01570 C (Me) 2 H Me HCOOH 13.5 92.5 94.7 3.6 78.5 78.9 TTNPB (1) (3) (1.3) (0.6) (4.6) (3.4) CB77787 SO2 OMe Me H COOH 102.9 125.1 117.9 163.3 110.2 119.8 (2.8) (2.6) (2.7) (11) (5.3) (801) CB5 ~ 757 S ~ 2 OHeptyl Me H COOH 0 110.9 107.6 0 145.6 105.5 (0) (8) (705) (0) (6.8) (5.6) CB71802 C (Me) 2 Me H Me COOH12,586.3 80.9 1 65.6 69.7 , (o, g) (4) (4.4) (0.5) (1.3) (2.4) CB12994 5 HH Me COOH53.2 89 92.1 4.4 93.6 107.3 (1.2) (2.2) (2) (l, l) (2.5) (2.4) CB39356 SO2 HH Me COOH72 104.8 104.8 70.7 128.9 124.2 (2.8) (2) (4.2) (1) (3.4) (3.1) CB73364 C (Me) 2 H HMe CONH- 0 151.4 155.6 0.1 87.2 92.7 tetra (0) (8.1) (6.4) (C, l) (2.4) (1.4) zoyl CB62458 C (~ e) 2 H HMe Tetra0 104.7 107.3 0 119 109.6 zoyl (0) (4.3) (3.7) (0) (7.8) (6.4) CB40747 C (Me) 2 Me HMe Tetra0 191.9 175.6 1.7 83.7 100.4 zoyl (0) (4.8) (4.8) (0.8) (3) (3.7) CB15068 S32 H HMeTetra 81.8 97.3 92.7 24.3 98 88.5 zoyl (1.2) (1.1) (3.3) (3) (5.2) (6.2) The level of proli ~ eration obtained for each line and for each product is expressed as a percentage compared to the controlled condition (100% + maximum, 6%
standard error on the mean).

CA 0224329 ~ l998-07-l3 W 097/26237 PCTn ~ 7/00079 _ 32 .

Table 6 below reports the results of the structure / activity study of compounds responding to the following general formula, on lines A549 and A-427:
R ~

~ R4 ~ Water ~ 6 A549 ¦ A-427 XlR7R6 X2 R5 R4 ~ 3 Rl 10-4M 10-6M 10 8M 10-4M 10-6M 10-8M
CB ~ 8528 C ~ Me) 2 CH HH MeCOOH 12.4 93.4 108.8 2.5 86.8 86.7 (1) (4.6) (3.7) (0.7) (3) (2.8) CB38416 C (Me) 2 NHH MeCOOH 109.3 104.7 126 24.1 105 105.8 (4.1) (6.4) (3.4) (1.8) (1.5) (2.7) CB36493 C (Me) 2 CH HH CF3COOH10,493,798.5 1.6 87.2 89.9 (1.4) (2.1) (2.9) (0.6) (4.2) (4.2) CB32706 C (Me) 2 CH Me H Me COOH 6103.2 101.4 0.8 99.6 102.9 (0.3) (2.3) (3.4) (0.6) (8) (3) CB62899 C (Me) 2 CH Me H CF3 COOH 0.45 118.8 131.2 0 123.8 115.4 (1,2) (2, ~) (4,2) (0) (7,7) (12) CB41666. a 'CH HH MeCOOH 63.2 89.9 94.5 7.6 91.2 83 (1.9) (2.3) (1.5) (i, 2) (6.6) (2.5) CB72489 S02 CH HH Me COOH 129.4 111.1 113.7 181.5 129.6 131.2 (2.6) (1.2) (4.1) (5) (2.8) (1.5) CB9 ~ 834 C (Me) 2CH HH MeTetra 14.4 108.8 104.7 3.1 78.3 80.5 zoyl (1.5) (4.5) (2.4) (0.5) ~ 3.3) (2.1) CB77402 C (Me) 2CH HH CF3 Tetra 10.7 86 93.1 0.2 77.6 82.3 zoyl (0.7) (7.4) (1.6) (0.1) (4.2) (5.4) CB61592 C (Me) 2CH Me H MeTetra 0 98.2105.60.60 107 104.7 zoyl (0) (2.9) (2.8) (0.6) (1.7) (2.8) CB63237 C (Me) 2CH Me H CF3 Tetra2,1140.2124 4.1 147.9 88.1 zoyl (0.9) (4.5) (5) (6) (12.4) (11.1) CB39122 SO2 CH HH MeTetra 84.8 98 96.2 27.1 96.5 93.9 zoyl (2.2) (1.2) (3) (2.7) (5) (3.1) The level of proli ~ eration obtained for each line and for each product is expressed as a percentage compared to the control condition ~ 100% + maximum, 6%
I () standard error on the mean).

CA 02243295 l998-07-l3 WO 9712623'7 PCTnFR97 ~ aOO79 .

Table 7 below reports the results of the structure / activity study of reference compounds CB16178, CB81808, CB13407, CB01570 and CB32934 on the lines A549 and A-427:
~ ~ Table 7 ~ 549 ~ ~ -427 ¦ Name 10-4M 10-6M 10-8M 10-4M 10-6M 10-8M
CB16178 AR-all-22,389.2 78.8 1.5 68.2 104.3 trans (0.9) (1.7) (2.1) (0.8) (10.8) (2.8) CB81808 AR-13-cis 23,685.9 77.66.5 99.6 100.3 (1) (2.5) (2.5) (1.5) (4.3) (3.6) CB1340 ~ AR-9-cls38 102.3 103.5 5.9 106.3 110.8 (1.3) (1.7) (1.5) (0, ~) (4.2) (3.6) CB01570 TTNPB13,592.5 94.7 3.6 78.5 78.9 (1) (3) (1.3) (0.6) (4.6) (3.4) CB32934 LGD1069 Q 118.3 134.2 0.4 102.3 108.9 (0) (3.9) (3.8) (0.3) (3.2) (6.2) The level of proliferation obtained for each line and for each product is expressed as a percentage compared to the control condition ~ 100% + maximum, 6%
I () of standard error on the mean).

Results for A549 Pulmonary Lianas and A-427.
The reference products are globally inactivate ifs on these lines at concentrations of 10 M and 10 8 M. Only the all-trans retinoid acid ~ eu (CB16178) and 13-cis-retinoic acid (CB81808) inhibits proliferation of the A549 line at 10 M and 10 M. The TTNPB (CB01570) inhibits the A-427 line at 10 M and at 10 ~ () M. Le BGD1069 (CB32934) induces stimulation of the proli ~ eration of A549 cells at 10 M and 10 M. Among derivatives including the R3 and R4 groups carried by the double bond between carbons 11 and 12 are of trans configuration, the compound CB71802 most inhibits ~ ortement the growth of these two pulmonary lines.
In contrast, stimulation of cell growth is observed with CB39356 (A-427), CB73364 (A54g) and CB40747 (A-427). The other molecules show little or no activity on these lines. Among the derivatives of formula CA 0224329 ~ 1998-07-13 W097 / 26237 ~ CT ~ FR97 / 00079 .

(I) according to the present invention, the compounds CB92834 and CB77402 have activity on the growth of these two lines. The other molecules do show no significant activity on these two bloodlines.
Results concerning lines m ~ mm ~ ires ZR-75-1 and T47D.
Among the reference products, acid 1 () all-trans retinoic (CB16178) and 13-cis acid retinoic (CB81808) like TTNPB (CB01570) inhibit cell growth of the two breast lines concentrations tested. 9-cis retinoic acid (CB13407) stimulates cell growth at 10 6 M and 10 8 M.
l ~ Dif ~ erent derivatives including R3 and R ~ carried by the double bond between carbons 11 and 12 are of trans configuration, like the compound CB62458 and the bioisosteres CB39356 and CB15068 do not influence the cell growth of the lines considered. ~ eul the ~ () compound CB73364 inhibits the growth of T-47D cells.
Among the derivatives of formula (I) con ~ ormes à la present invention, the compound CB92834 shows a ~ toe cell growth inhibitory activity of both lines The other molecules are less powerful 'see ~ inactive Conclusions.
a) MTT test:
Among the reference retinoids tested all-trans retinoic acid (CB16178), 13-cis acid retinoic (CB81808), 9-cis-retinoic acid ~ eu (CB13407), TTNPB (CB01570) and LGD1069 (CB32934), induced TTNPB
strongest inhibition of cell lines. The product CB92834 appears as active on the MTT test as . the reference products tested. The compound CB92834 is more active on estrogen-sensitive lines such as lines m ~ mm ~ ires ZR-75-1 and T-47D only on lines CA 0224329 ~ l998-07-l3 WO 97126 ~ 37 PCT / P ~ 97/00079 The antiproliferative activity of CB92834 on mammary tumor lines, determined in vitro at using the MTT test, is found and correlated to the results obtained on the SAMBA image analysis system. These two different techniques thus highlight the activity anti-neoplastic of this retinoid.
Quantitative analysis of the image of nuclei stained in a specific and stoichiometric way is based on the calculation of 15 determined morphonuclear parameters either 1 (3 from:
- the density values histogram optical, - section length matrices, - co-occurrence matrices 1 ~ Statistical processing of the data obtained allows to determine and characterize the activity ~ ntitumoral retinoids at the level:
- the proli ~ eration index, - cell kinetics, '() - the organization of the distribution and texture of chromatin.

b) SAMBA test:
Image analysis of the colored nuclei allows "d ~ get a DNA histogram and calculate an index proliferation. In addition to studying the kinetics of cell cycle, image analysis of these nuclei at through the measurement of 15 parameters and the quantification of chromatin allows to determine influence of the drug on a cytological state of differentiation.
TTNPB (CB01570) and compound CB92834 influence morphological differentiation differently of the line ~ -47D while their inhibition capacities ~: - global cell proliferation (MTT test) of neoplastic cells are found to be comparable. The dose effect CA 0224329 ~ 1998-07-13 W 097/26237 PCTn ~ Rg7 / 00079 depending on the TTNPB on the value of the different parameters morphonuclear treated in multivariate analysis suggests strongly a direct correlation between the cytotoxic effect of the molecule and its anti-tumor activity. Conversely the anti-tumor effect of CB92834 is not linked to an effect cytotoxic but with a modulation of the gain ratio cell loss and cell induction cell ~ differentiation.
The TTNPB (CB01570) operates 1 () antitumor by a direct cytotoxic (cytocidal) effect while the anti-tumor power of the compound CB92834 would be mediated by activation of cell death and / or inhibition of proliferation due to the induction of a cell differentiation.
1 ~ The derivatives of formula (I), and more especially the compounds CB92 ~ 34 and CB77402, therefore point out with interesting properties pharmacological, and can therefore be used in human or animal therapy as a medicine as well ~ () only in cosmetology.

B) Clonoaenic tests. _ = =
By de ~ inition a cell is considered =
clonogenic if it has the ability to proliferate and give birth to a cell colony containing at minimum 50 cells. "Human tumor stem cells" or "human tumor stem cells" are cells clonogenic which are at the origin: neoplastic cells which constitute a given tumor. These stem cells .- () tumors are responsible for recurrence processes observable after surgical resection of tumors primary schools and are also responsible for the training of metastases. They have thus become the first target of certain anticancer chemotherapies (Fialkow PJ and . ~ al., Am. J. Med., 1977, 63, 125-13Q; Hamburger AW and Salmon SE, Science, 1977, 197, 461-463; Selby P. et al., CA 0224329 ~ 1998-07-13 W O9 ~ J2623'7 PCT ~ R97100079 .

N. England J. Med., 1983, 308, 129 134; Steel GG, Growth kinetics of tumor, Clarendon Press, 1977). At a level tumor or tumor cell line these cells clonogenic strains differentiate from other cells clonogenic tumor or cell line neoplastic co ~ stunned, by the fact that they retain their ability to proliferate in the absence of any solid support.
A simple method called "clonogenic test"
(colony-forming assays or stem cell assay) has been developed 1 () in 1977 by Hamburger AH and Salmon SE This technique is suitable for in vitro culture of most tumors and tumor cell lines from various ~ istological types. As part of this test, neoplastic cells are cultured on a 1 ~ semi-solid "soft agar" culture medium consisting of mixture of agar and agarose On this selective support, do not subsist and only grow stem cells tumor. Indeed, on such a culture medium the normal cells, such as fibroblasts, do not () do not survive Under these conditions, depending on the tumor or the tumor cell line considered, the percentage of tumor cells capable of proliferating and to give birth to a cell colony is understood between 0.1 and ~, 001% only. Characteristics . ~ morphology and growth of cell colonies are also a function of the histological type of tumors considered.
This technique remains the most commonly used and best suited to the study of the effects of () anticancer drugs on tumor stem cells humai] the indeed the first in vitro studies doing call this type of test indicate that a correct prediction response to chemotherapy treatment is possible in about 60% of cases and that a correct prediction of the ~~ resistance of a tumor to chemotherapy treatment can be highlighted in more than 90% of cases (Van CA 0224329 ~ 1998-07-13 WO 97/26237 PCTn ~ R97 / 00079 _ 38 .

~ loff DD, Semin. Oncol. 1985, 12, 327-331; Bertelsen CA, Cancer, 198 ~, 53, 1240-1245) This test makes it possible to study and describe biological properties, sensitivity to different anticancer agents used in chemotherapy.
For the same patient, this test allows to study heterogeneity in response to a given drug within of the same tumor, between the primary tumor and its metastases and finally between the different metastases ~ Tanigawa N. et al. Cancer Res., 1984, 44, 2309-23 ~ 2).
I () The study of clonogenic growth of tumor cells of a given tumor on a semi-solid culture medium seems to be related to the degree of malignancy of the tumor considered (Dittrich C. et al, J. Clin. Oncol 1991, 9, 381-38 ~; Von Ho ~ f DD et al., Cancer Res. 1983, 43, 1926-I ~ 1931; Alberts DS et al., Lancet, 1980, 2, 340-343;
Meyskens FL et al. Br J. Cancer, 1981, 44, 787-797;
Salmon SE et al. Cancer Research, 1980 ', 74, 300-305;
Salmon SE et al., Cloning of human tumor stem cells, 1980, 223-245; Von Hof ~ 3.D. et al., Am. J. Med. 1981, 70.1027-'() 1032).
In the context of the invention, the influence of various retinoids on cell colony growth obtained by cultivating the T-47D breast tumor line on this semi-solid "soft-agar" culture medium was measured These culture conditions are also called ~ anchorage-independent ".

1) Materials and methods.
a) Reagents, culture medium and vine ~ () cellulai ~ e tumor.
- Reagents.
The derivatives of the invention and the products of benchmarks tested were synthesized according to the procedures which will be described later or according to known methods of . ~ the skilled person.

W 097 / 2623'7 PCT ~ FR97 / ~ 0079 Commercial tamoxifen, designated CB58707, and

4-hydroxytamoxifene, designated CB05764, have been acquired from from Sigma (Saint Quentin Fallavier, France).
Several reference retinoids, ligands of two classes of nuclear receptors RAR and RXR known from Those skilled in the art, were selected:
- 9-cis retinoic acid, a natural ligand, designated CB13407.
- The TTNPB designated CB01570.
I () - An analog of TTNPB SRI designated CB28628.
- The LGD1069 designated CB32934.
- Culture centre.
The base medium "MEM 25 MM HEPES" (Minimum Essential Medium, Life technologies, selgique) contains Eagle salts but no L-glutamine. This environment is good suitable for growing a range of varied cells diploid or primary mammalian. ~ th middle is then added :
- a ~ 5% amount of SVF (Calf Serum '() Fetal, Li ~ e Technologies, selgique) decomplemented at 56 ~ C
for 1 hour, - 0.6 mg / ml of L-glutamine (Life Technologies, Belgium ), - 200 IU / ml of penicillin (Life Technologies, Belyique), - 200 ~ g / ml of streptomycin (Life Technologies, Belgium), - 0.1 mg / ml gentamicin (Life Technologies, Belgium).
~ () - Tumor cell line.
The original human tumor cell line T-47D breast used in this work comes from ATCC (American Type Culture Collection, ATCC code: HTB
133) CA 0224329 ~ 1998-07-13 W097t26237 PCT ~ FR97100079 _ 40 b) Experimental protocols.
Tumor cells are kept in culture in 25 cm2 falcon boxes ~ Li ~ e Technologies, Belgium) They are then trypsinized and . ~ individualized Their viability rate is determined by staining with trypan blue (Sigma, Belgium). He must be greater than 90%. In case this condition is respected a cell suspension at the concentration desired is prepared in a 0.3 g agar solution. The 1 () cells are then seeded between two layers of agar (Sigma, Belgium) and in 35 mm Petri dishes (Life Technologies, Belgium). The base layer consists d ~ 0.5% agar solution and the top layer is consisting of a 0.3% agar solution. The cups are 1. ~ then placed and maintained in an incubator at 37 ~ C and

5% CO ~. Twenty four hours after sowing, the cells are treated by depositing on the top layer the different products to be tested at concentrations 100 ~ be greater than the desired final concentration because the ~ () volume of the added treatment solution is 100 times less than the total volume of agar deposited in the boxes of Petri dish. After the treatment the cups are kept in the incubator for 21 days. It is advisable to consider, during experimentation, onset and growth cell colonies If after 10 days no colony does not appear or develop the experiment must be renewed. Otherwise on the 21st day 100 ~ 1 of a MTT solution (3- (4,5-dimethylthiazol-2-yl) -2,5 diphenyl tetrazolium bromide; Sigma, Belgium) dissolved in ~ () culture medium RPMI (Roswell Park Memorial Institute, Life technologies, Belgium) at the concentration of lmg / ml are deposited on the upper layer of all The cells are kept in contact with this solution at least 3 hours at 37 ~ C. Cells metabolically active then transform by reduction mitochondrial this yellowish solution in blue crystals of CA 02243295 l998-07-l3 WO 97/26 ~ 3'7 4I PCT ~ R97 / 00079 formazar thus allowing to highlight the colonies cells present (Mosmann, 1983; Carmichael et al., 1987).
Using an inverted and low microscope magnification the number of clones whose surface is greater than 100 ~ m is determined in all of the cups representing all of the different conditions experimental. Then for each of these conditions the average number of cell colonies +
standard error on the mean (ESM) is calculated.

c) Statistical analysis.
The results obtained under the conditions processed are compared to those obtained under the condition 1 ~ control through a statistical analysis of non parametric type and according to the Mann-Withney test (NS:
P>0.05; *: P <0.05; **: P <0.01; * ~ *: P <0.001).

2) Results.
~ () The results are reported in Tables 8 to 10. The average number of cell colonies determined for each experimental condition is expressed as a percentage in relation to the control condition set equal to 100%.

'. a) Results concerning ~ roducts reference.
Table 8 below groups the results obtained with the chosen reference products.
Table 8 ~) Cell line ~ laire ~ -47D
Code Name 10-7 M lo-8 M10 9 Mlo-10 M
CB58707 Tamoxifen 31.3 + 46.9 + 35.5 + 56.7 +
3.9 (*) 2.6 (*) 4.2 (*) 3.4 (*) CB01570 TTNPB 1.3 + 2.1 + 5.5 + 3 ~, 1 +
0.2 (*) 0.4 (*) 1 (*) 7.9 (*) CB13407 9-cis RA6.7 +45.6 +52.8 + 54.9 +
1.8 (*) 4.8 (*) 3.9 (*) 7.2 (*) CB05764 4-HPR 18.8 +33.6 +83.3 + 80.3 +
1.1 (*) 3 (*) 7.3 (NS) 12.9 (NS) CA 0224329 ~ l998-07-l3 WO 97/26237 PCT ~ FRg7 / 00079 CB32934 LGD1069 No 24.7 + 31.1 + 37 +
tested 3.3 (~) 0.3 (*) 9.3 (~) CB28628 Analog of 21.4 + 97.6 + 89.2 ~ No SRI TTNPB 2.4 (~) 6.6 (NS) 3.6 (NS) tested The results obtained show that the products chosen benchmarks inhibit differently the growth of cell colonies of the tumor line human breast T-47D.
Tamoxifen (CB58707), molecule with activity anti-estrogenic, induced at the concentrations tested here (10 7 M to 10 10 M) significant inhibition of growth of these colonies but its activity is not dose dependent, this ~ ui is not the case of its counterpart on 4-I () IIPR. The latter, very strongly active at the concentration of 10 7 M, loses its signi ~ icant inhibitory activity as soon as concentration of 10 M. The natural 9-cis acid retinoid retinoic (CB13407) has inhibitory activity significant and dose dependent. In: Ein the retinoid 1 synthétic ~ eu TTNPB (CB01570) very strongly inhibits, so significant and dose dependent the growth of cell colonies of the T-47D line. It is to highlight that its inhibitory activity is still 66% at the concentration of 10 M. The LGD1069, specific ligand of ~ () RXR nuclear receptors, inhibits Eortement and significantly the growth of cell colonies of the T-47D line. If its inhibitory activity is weak dependent dose, it nevertheless remains very important at concentration of 10 M (6396). The retinoid SRI-CB28628 ~ f ~ strongly and significantly inhibits the growth of cell colonies at the concentration of 10 7 M but loses ~ very quickly its activity, from the concentration of .- () b) Results concerning ~ roducts of the series (E) Table 9 below summarizes all of the results for trans (E) series retinoids.

CA 02243295 l998-07-l3 WO 9712623'1 PCT ~ FrR97 ~ 0007 Table ~ u ~
T-47D cell line Code 1o-8 M 10-9 M lo-10 M
CB1227371.2 i93.9 + 92.9 +
2.9 (*) 3.3NS) 21.7 (NS) CB4034165.6 +90.8 + 99.1 +
9.5 (*) 0.8 (NS) 9, 7 (NS) CB7123958 + 86.6 + 95.5 +
4.1 (*) 9.4 (NS) 1.7 (NS) CB3897338.6 +60.1 f 68.4 +
3, 6 (*) 2 (*) 8.3 (*) CB5720164, 8 +58.9 + 75.2 +
1.2 (*) 11 (*) 12.2 ~ NS) CB7180245, 2 i92.5 + 104.3 +
4.8 (*) 9.6 (NS) 2.3 (NS) CB7336410.3 i54.9 + 99.3 +
2.8 (*) 5.8 (*) 7.8 (NS) The arotinoids of this trans series (E) induce inhibition of colony growth of the T-47D line significantly at the concentration of 10 to 8 M. At this concentration the percentage inhibition of the different products is spread out from 69.7% for the product CB73364 to 28.8% for the product CB12273. At the concentration of 10 M only three (CB38973, I () CB57201 and CB73364) on the seven products tested inhibit the growth of cell colonies. At the concentration of 10 1 M, only two products (CB38973 and CB57201) on the seven products significantly inhibit growth colonies at these two concentrations of 10 9 M and 1 ~ 10 10 M, none of the induced inhibitions is greater than 50%.

c) Results concerning the products of the series cis (Z).
~ () Table 10 below summarizes all of the results for the cis (Z) series retinoids.
Table 10 ¦ T-47D cell line ¦Code ¦10-8 M ¦ 10-9 M ¦ 10-1 ~ M ¦

CA 0224329 ~ 1998-07-13 W 097/26237 PCT ~ R97100079 CB02981 4 ~, 8 + 67.6 + 80.1 +
5.3 (*) 8.9 (MS) 13.2 (NS) CB36493 17.4 + 24.8 + 35.8 +
2 (*) 0.5 (*) 3.2 (*) CB61692 55.7 + 41.5 + 90.3 + =
2.6 (*) 5.7 (*) 4.7 (NS) CB92834 38 + 58.9 + 82.5 +
2 (*) 3.7 (NS) 12 (NS) Code 10-7 M lo-8 M 10-9 M
CB16279 101.7 +989.8 + 110.1 +
3.4 (NS) 3.7 (NS) 1.5 (NS) CB38416 11.6 + 15.3 + 20 +
1.9 (*) 1.7 (*) 0.2 (*) Among the six products tested in this series, product CB16279 does not induce any significant modification growth of cell colonies and even at concentration of 10 M. However, the other five products induce at a concentration of 10 8 M a significant inhibition of the growth of these colonies.
At ~ concentrations of 10 9 M and 10 M three products (CB
36493, CB61692 and CB38416) out of six and one product (CB36493) on ~ other significantly inhibit the growth of cell colonies of the T-47D tumor line. At these two concentrations the inhibitions induced by products CB 36493, CB 61692 and CB 38416 are all greater than 50%.

I- 3) Discussion and conclusion.
The above results show that the test clonogenic is a test suitable for selection and screnning of various retinoids.
Under the same experimental conditions, the ~) inhibitions induced by cis series products (Z) on the growth of cell colonies in the line T-47D human breast tumor grown on soft agar are for the most part significantly more important than those induced by the products of the trans (E) series. We "notice that the product CB92834 has activity global inhibitor and dependent dose as large as WO 97126237 PCT / ~ R97 / 00079 .

that obtained with the best products of the trans series (E). The products of the cis (Z) series are presented as stronger inhibitors of cell growth tumor strains of the T-47D line as the products of the trans series (E). In addition, the products CB36493 and CB3 ~ 416 from the cis (Z) series appear as active as the products CB13407 (9-cis RA) and LGD1069. Finally only the reference product TTNPB (CB01570) is more active ~ ue product cs36493 of the cis series (Z).
I () II - Activities of derivatives of ~ ormule (I) on recent: retinoidal and certain factors transcriptional. . , I) Models and reference molecules.
I ~ All trans retinoic acid (ttRA) and its 9-cis, 11-cis and 13-cis stereoisomers bind and activate, more or less selectively, intranuclear receptors called retinoic receptors. An important advance in the molecular action mechanism of the transduction signal 1 retinoic acid was established in particular thanks to the work The shareholders of RM Evans et al. (Sciences, 1988, 240, 889-~ 95).
The compounds of the invention of the retinoid type or arotinoids have different selectivity profiles 3 ~ vis-à-vis the retinoic acid receptor subtypes (RARs) and retinoid X receptors (RXRs).
A large number of recent clinical results have shown that retinoic acid, some of its isomers and derivatives forming the retinoid class, are ~ (~ used for the treatment of diseases such as acne, psoriasis and certain cancers (U. Reichert et al, Pharmacology of Retinoids in the Skin, Karger AG Eds, Basel, J 1989; MS Tallman et al, Retinoids in Cancer Treatment, J.
Clin Pharmacol., 1992, 32, 868-888 i Warrell et al, N.
~~ Engl. J. Med., 1991, 324, 1385-1393).

CA 0224329 ~ 1998-07-13 These retinoids are also evaluated in other therapeutic areas such as, for information only arthritis (Vinienti MP et al, Using Inhibitors of Metalloproteinases to treat Arthritis, Arthritis Rheumatoidism, 199 ~, 37, 1115-1126); dyslipidemia (Rottman et al, A RARE Element in the Apolipoprotein AI Gene Distinguishes Between Two Different Retinoic Acid Response Pathways, Mol. Cell. Biol, 1991, 3814-3820); prevention of HIV induced lymphopenia (Yang Y. et al, 9-cis RA
1 () Inhibits Activation-Driven T-Cell Apoptosis: Implications ~ or Retinoid X Receptor Involvement in Thymocyte ~ evelopment, Proc Natl Acad Sci USA, 1993, 90, 6170-6174 ~. These therapeutic effects result from the ability to retinoic acid and certain retinoids to control 1 ~ abnormal cellular situations by the modulation of cell growth, cell differentiation and / or apoptosis or programmed cell death (The Retinoids, Biology, Chemistry and Medicine, MB Sporn, AB
Roberts and DS Goodman, Raven Press Eds, 2nd ed, New York '~) 1994). These regulations have been largely attributed ~ formation of ligand-receptor complexes Ces proteins belong to the ~ receptor superfamily nuclear, and function as transcription factors dependent ligands. It is these interactions that are responsible for transcriptional activation and associated physiological effects.
Using endogenous and synthetic ligands, this family has been classified into two series called RAR and RXR, each composed of three receptor subtypes ~ () called ~, ~ and ~. In addition, these retinoids have been shown able to regulate the expression of other genes by an effect inhibitor of transcriptional factors like complex AP-1 composed of the oncogenic proteins c-Fos and c-Jun All these receptor proteins modulate the expression of certain genes by selective binding, in the form of a dimer, to specific regions of DNA called RARE's (for Retinoic WO 97/26237 PCT ~ FR97 / 00079 47 Acid Response Element's, M B. Sporn et al, p 319-349, DJ
rIangeisdorf et al, Proc Natl Acad Sci USA, 1991, 88, 3559-3563) RXR receivers work as homodimers or can heterodimerize with RAR receptors as well than with other members of the receptor superfamily intracellular All trans retinoic acid (ttRA) is the The natural igand of RAR receptors, while its isomer 9-I () cis (9 - cis RA) is both a ligand for RXRs receptors and ~ ARs in the form ~ 'homodimers and heterodimers (MB
Sporn, page 5-178, XK. Zhang et al, Homodimer formation of Retinoid X receptor induced by 9-cis RA, Nature, 1992, 358, 587-59: l, Heyman RA et al, 9-cis RA is a high affinity l ~ ligand for the Retinoic Receptor X, Cell, 1992, 68, 397-406, Levin AA et al, 9-cis RA stereoisomer binds and activates the nuclear receptor RXRa, Matu ~ e, 1992, 355, 359-361) These receptors have been shown to be significantly different: the primary structures of ~) domains of 1; aisons (amino acid composition) are different to more than 80 ~ Similarly, a distribution different from these receptor subtypes is a function of the nature of the tissues For example, RARs are not expressed in the viscera, however the RXRa mRNA are "most abundant in the liver, kidneys, lungs, the gut and muscles.
The hormone-dependent pathways of RARs can be activated by specific R ~ R ligands which bind to RAR paltie of heterodimeric RAR-RXRs, while ~ () specific iigands RXR appears to be unable to activate these same pathways by binding to the RXR part of the RXR ligands have an activation synergy of genes responding to - ttRA when used in combination with ligands specific RARs (Roy B. et al, Mol. Cell Biol., 1995, 15, R81Rs form homodimers, in the presence of RXR ligands and regulate the transcription of genes that are CA 0224329 ~ 1998-07-13 WO 97/26237 PCT ~ 7/00079 distinct from those controlled by RAR-RXR heterodimers (Zhang X.-K. et al. Cited above).
So retinoids which are selective for receptor subtypes will be useful for control selective see independent of mediated physiological pathways by these same subtypes. By comparison a panagonist will be useful for controlling the mediated physiological pathways by several of these subtypes. It appears that retinoids acting selectively on these subtypes IOs may increase therapeutic efficacy and reduce the ~ Profile of side effects. A panagonist is defined c: as an agent which binds and activates at least one of receptors of the RAR subfamily and of the RXR subfamily.
the true panagonist activates all members of the sub 1 ~ RAR and RXR families.
All trans retinoic acid (ttRA ~, as its ~ somers 13-cis, has during any chronic treatment a powerful effect of hypervitaminosis, mucocutaneous toxicity and of teratogenicity. In addition, ttRA induces its own ~ () metabolism which has the direct effect of decreasing quickly its therapeutic efficacy.
This is why, the present invention aims to spin new compounds with greater stability chemical and metabolic, and activity profiles different with respect to these linked receptor subtypes has anti-tumor and anti-proliferative activities well-established selectives. Such a strategy has led to the ~ ormation of molecules:
- RAR-RXR panagonists, ~ () - selective RAR or RXR, - anti-AP-1 dissociants.
By their own co-activatio ~ property RAR proteins, RXR-selective retinoids constitute a again more therapeutic. At doses where they are inactive ~~ by themselves, they can increase the activity of RAR-selective retinoids, and in particular RAR ~, then useful WO 97/26237 PCTnFR97 / 0007 in the treatment (regression or remission) of cancer leukemia type, solid tumors, more particularly breast, head and neck, but also more classic in episodes of acne, severe acne and skin damaged by the sun. Retinoid administration used in combination, can be concomitant or simultaneous. In this case, the administrative gap between the retinoids should not exceed a few hours, such so that the RXR and RAR retinoids would be in 1 () healthy concentrations such as potentiation either effective.

1) Ex ~ ression of receivers ~ RAR. RXR and RE in function of cell vines.
I ~ MCF-7 and HeLa cells are grown in DMEM with phenol red supplemented with fetal calf serum 5 ~. T47-D cells are grown in RPMI
additi ~ born of calf serum ~ oetal 10%. ~ es tests are carried out in DMEM without red 'o phenol with carbon-treated fetal calf serum 3% dextran. ~ Açon transfected cell lines : -, table, from MCF-7 and HeLa lines, are established according to the protocol described by D. Gagne et al (J. Biolumin.
Chemilumin., 1994, 9, 201-209). Experiments using "the various retinoids are produced free from light to avoid any isomerization.
Table 11 below reports the difference for expression of retinoic acid receptors and RE estrogen receptor by HeLa and MCF-7 cells ~ () (Titco ~ b MW et al., Mol. Endocrinol., 1994, 8, 870-877 ~.
The results of Table 11 are expressed in fentomoles of receptor per mg of protein.
Table 11 Receiver type HeLa MCF-7 ER not detected expressed RAR ~ 28 80 CA 0224329 ~ 1998-07-13 WO 97/26237 P ~ TnFR97100079 -RAR ~ 9 not detected RARy 16 34 RXRa 50 12 RXR ~ 28 not detected =
RXR ~ 9 not detected 2) S ~ specificity of the reference molecules in ~ - ~ es transient transfections models.
a) Gal4-RAR chimeric receptors.
Transactivating specificity studies of L-etinoids were produced by transient transfection of cells ~ eLa Two types of chimeric receptors ~ eu p ~ euvent then be expressed by cells. Plasmids ~ al-~ ARa Gal-RAR ~ and Gal-RARy (JY Chen et al. EM30 J. 1995 1187-1197) encode Gal4- chimeric receptors ~ AR in which the DNA binding domain of the ~ yeast Gal4 rotein is fused with regions E and F
! regions containing the ligand binding domain and the AF-2) activation receptor for acid receptors Letinique. Region C (DNA binding domain) and the regions A and B (AF-1 activation domain) are deleted.
These chimeric receptors activated by a .lyonist specifically stimulate gene transcription ~ -1e the luciferase present in a cotransfected plasmid '() ~ (17M) s- ~ G-Luc) where 17M is the answer element ~ e Gal4. The transcriptional cooperativity between AF-1 and AF-2 does not exist ~ ace with this type of receiver The use of reference molecules allowed to check the validity of the GAL-RAR model to determine the "specificity of agonist molecules: this GAL-RAR model reducts the ~ purpose of a compound for the binding domain to the RAR hormone. The arotinoid TTNPB in concentration M is used as a transactivation reference maximum (100%) obtained with a synthetic agonist. So ~ () TTNPB and tt ~ A are good RAR agonists while ~ ue Am580 behaves well as a RARa specific to concentration WO 97126 ~ 37 PCT ~ F'R97 / 00079 ~ 1 10 nM. Compounds described as specific RXR
(LGD1069 and LGD-CB14499) do not allow to observe a good transactivation mediated by RAR Table 12 below--below reports these results, where the activity of the compounds is expressed as a percentage of the activity measured for the TTNPB 10-8 M.
The compound designated AmS80 is 4 - [(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carboxamido] benzoic (Shudo K. et al., J. Med. Chem., 1988, 31, 2182-219-2).
Table 12 GALq-RAR
Product Concentration RARa RAR ~ RAR ~
(Log M) (%) (%) (%) -8 82 1 ~ 9 106 ttRA -7 102 93 104

-6 108 92 111 Am580 -7 102 77 64 L5D- -8 l 0 0 C'B14499 -7 4 1 0 b) ER-cassette chimeric receivers. The RAR-ER chimeric receptors have been described by Petkovitch et al. (Nature, 1987, 330, 444-450). Cells HeLa are cotransfected with a plasmid which codes for a retinoic receptor in which the C domain binding to DNA is substituted by that of the estrogen receptor RE, and a plasmid that places the expression of luciferase under the control of an ERE (Response Element to estrogens). The chimeric receptors expressed are designated as RARa-ERcassette ~ RAR ~ -ERcassette, RAR ~ -CA 0224329 ~ 1998-07-13 W 097/26237 PCTnFR97 / 00079 .

ERcassette and RXR ~ -ERcassette. Regions A, B, D, E and F
of the natural receptor are retained as well as the cross-functional cooperation between fields AF-1 and AF-2 activation. These transfections experiences transients follow the co-precipitation method at calcium phosphate. HeLa cells are cotransfected with 0.25 mg of plasmid coding for the chimeric receptor, 1 mg of reporter plasmid and 0.5 mg of CMV- ~ -galactosidase expression vector used as an internal transfection control. 29 hours after transfection, cells are incubated for 16 hours with the different effectors.
In this type of chimeric receptor, the domain C binding to RAR DNA is substituted by that of RE estrogen receptor. The protein obtained is close of the natural RAR receptor and retains the properties AF-1 and AF-2 transcriptional domains. = It modulates transcription through an ERE. This model RAR-ERcassette allows to observe a response transcriptional to a more physiological ligand The effect of natural hormones ~ ttRA and 9-cis RA) is remarkable. These ligznds induce an overexpression luciferase compared to induction caused by a synthetic compound (TTNPB). This phenomenon is also observed on other responses (see in particular results of transactivation on HRLN models). This shows that the RAR-ER constructions cassettes reflect a context physiological. The RAR specificity of Am580 is again found for concentrations below 10 nM. The profile defined in RAR - ERcassette for agonists RXR (LGD1069 and LGD-CB14499) differs from their GAL-RAR profile.
Compared to TTNPB, their transcriptional power appears higher, in particular through RAR ~ -ERassette. This result can be explained by a heterodimerization of RAR-ERcassette with RXR receptors endogenous expressed by transfected HeLa cells.

W 097/26237 PCT ~ R97JO0 ~ 79 -LGD1069 l ~ M allows a coactivation of RAR and RXR, causing an overactivation of the heterodimer compared to specific RAR activation of TTNPB. The RAR model--ERcassette therefore translates a RAR activity of a compound and also an RXR activity. So any panagonist molecule results in a maximum transcription greater than that of TTNPB. This observation is confirmed by the fact that if a specific RAR molecule is associated with an RXR molecule specific, overexpression of luciferase occurs.
The use of the RAR-ERcassette construction thus allows to visualize and highlight an RXR activity like reported in Table 13 below.
Table 13 RAR-ERca- ~ settes Product Concentration (LogM) RAR ~ (~) RAR ~ (~) RARy (%) ttRA -8 127 128 119

-7 249 270 122 9-cis RA -8 60 94 56 -6,348,369,157 Am580 -8 113 7 ~ 45

-8 14 78 19 3) ~ .effect of reference retinoids on the estrogen-adult proliferation - T, ignees cellul ~ ires MCF-7 and T-47D.
In order to test the antiproliferative effect of retinoids, growth experiences under conditions CA 0224329 ~ 1998-07-13 WO 97/26237 PCTA ~ R97 / 00079 estrogens on MCF-7 and T-47D cells have been carried out. These are breast cancer cells estrogen-dependent humans that express the receptor to RE estrogens. The effect of the molecules is evaluated after 7 5 days of culture in estrogenic conditions (estradiol 10-

9 M) by assaying cellular DNA. ~ Cells are distributed in 24-well plates at a density of ~ .104 cells per well. Trials with the various retinoids are made in triplicate and the culture medium is changed after 4 days of growth. Cell DNA is measured by the 4,6-diamidino-2-phenylindole (CF) method Brunck et al., Anal Biochem., 1979, 92, 497-500). The activity of compounds is expressed as a percentage, 100 ~ representing the amount of DNA measured with estradiol 10-9 M.
The ta ~ leau 14 below presents the retinoid concentrations needed to inhibit 50 ~
MCF-7 and T-47D cell growth, or the percentage growth inhibition at the concentration of 1 ~ M. The specific RAR molecules (TTNPB and Am580) have an effect more ort inhibitor than natural ligands (ttRA and 9-cis RA) and that LGD1069 (RXR agonist). These results confirm those reported by Dawson et al. , Cancer Res, 1995, 55, 446-451, who have shown that RARa agonists are effective inhibitors of cell growth = MCF-7, and that the retinoid affinity for RARa is closely-correlated with their anti-proliferative activity. To the concentration of 10 8 M, LGD1069 is specific RXRa and has no effect on growth under condition estrogen of MCF-7 and T-47D cells.
Sheet 14 EFF.T ANTIPROL: IFERATIVE
Product T ~ 47D MCF-7 IC50 (nM) ICso (nM) ttRA 39.1 14.1 - / - 10.3 9-cis RA25.1 + / -1.4 Not finished Am580 74% ~ 7%
TTNPB 3.3 +/- 1.10.35 +/- 0.07 CA 0224329 ~ 1998-07-13 WO 97/2623 ~ 7 PCT ~ R97 ~ aa79 ¦LGD1069 20% ~ 33 ~ l Some properties of retinoids have been determined thanks to more elaborate cellular models.
These models consist of cell lines stably transfected with recombinant plasmids that place the expression of the luciferase gene under the control of various elements of nuclear response. The observed effects then correspond to regulations physiological and endogenous receptor activity.
The duplicate tests are described below for each of these models.

4) Transactivating activity of retinoids ~ e refererlce me ~ iée by retinoï acid receptors ~ eu -T, igneous ~ cellular HRT, N and HRT, + N transfected st ~ le.
The HRLN and HRI. + N cell lines allow to study the activation of a RARE by receptors endogenous using ligands at concentrations physiological. These lines are derived from HeLa cells stably transfected with a reporter gene which places expression of the luci ~ erase gene under control of a RARE nuclear response element (RARE3-tk-Luc). The HeLa cells express all acid receptors known retinoic (RAR ~, ~, ~ and R ~ R ~, ~, y) with a predominance of RARa and RXR ~. The RARE response element used for HRLN cells corresponds to the natural gene sequence of the RAR ~ receiver (GGTTCAnnnnnAGTTCA). HRL + N cells have the sequence GAGTGAnnnnnCGGTGA.
a) Line ~ RT, N.
This line includes the RARE response element of the natural gene for the RAR ~ receptor which controls expression - the luci ~ erase gene. ttRA and 9-cis RA induce a dose-dependent activation. Over-activation compared to TTNPB is observed at high concentration (1 ~ M), comparable CA 0224329 ~ 1998-07-13 WO 97/26237 PCT ~ FR97 / 00079 _ 56 .
-to that observed with ERcassettes constructions. Unecoactlvation of RAR and RXR at the heterodimer level is certainly involved.
The results for TTNPB and Am580 indicate activation specifically induced by RAR receptors.
The ECso of these two molecules are similar Am580 induced a transactivation mediated by RARa and TTNPB by RAR ~, ~
as shown by the use of the antagonist RAR ~ Ro 41-5253 (Apfel, C. et al., PNAS, USA, 1992, 89, 7129-7133) which totally abolishes the response of Am580 and partially that TTNPB. However, RAR ~ appears as the receiver predominant for transactivation in HeLa cells.
The ligand RXR ~ specifi ~ eu LGDl069 transactive with an ECso of ~ 10 nM, which corresponds to its RXR activity. Line HRLN makes it possible to clearly highlight an activity Physiological RAR of the compounds, but low RXR activity is observed. Table 15 below reports these results where the expression 100 ~ corresponds to the induction caused by TTNPB 10-8 M. The ECso are determined to from the results obtained with a range of concentrations ranging from 1 nM to 1 ~ M.
Table ~ u 15 HRLN TRANSACTIVATION
Product E maY% EC ~ o lnM) ttRA 20 ~ 2.5 +/- 9 9-cis RA 19 ~ not determined Am580 10 ~ 0.10 +/- 0.06 TTNPB 100 0.55 +/- 0.72 LGDl069 73 9.4 +/- 6.3 LGD-CB14499 30 not determined .

b) T, igneous HRT + N.
The transactivation results obtained with the HRL + N line are comparable to those obtained with the line HRLN for RAR agonist molecules (TTNPB and Am580) and natural ligands (ttRA and 9-cis RA). RXR agonists (LGD1069 and LGD-CBl4499) induce more transactivation strong with = HRL + N and LGDl069 cells 1 ~ M is more WO 97 / 2623'7 PCT ~ FR97 / 00079 _ 57 .

effective than RAR speci: Eiques molecules. Furthermore, the association of a RAR agonist and an RXR agonist (by example TTNPB + LGD-CB14499, figure 1 in appendix) allows a better transactivation than that caused by each S molecule used separately. The HRL ~ N line allows visualize co-activation of the RAR and RXR receptors at level of the RAR - RXR heterodimer. Thus, LGD1069 1 ~ M having a RAR activity at this concentration behaves like a panagonist. This ~ result should be correlated with over-activation induced by RXR agonist molecules with models RAR-ER cassettes. The HRL + N line clearly allows evidence of RAR and RX ~ activity of the molecules. These results are reported in Table 16 below where the transcriptional activity of the products is expressed in percentage, 100% corresponding to the level of activity measured in the presence of TTNPB 10--8 M.
Table l ~
HRL + N TRANSACTIVATION
Product (10-6 M) Emax (%) ttRA 225 Am580 99 TTNPB (10-8 M) 100 LGDl069 131 Figure 1 in the appendix shows the over-activation induced by a selective RXR molecule in the presence of a agonis ~ e RAR speci ~ ic on the HRL + N model.

5) Anti-AP-1 Effect of Reference Retinoids on estrogen-dependent cells activated by TPA -T ~ i ~ born cell MTL ~.
The anti-factor AP-1 transrepressant effect of retinoids is determined using the MTLN line, derived MCF-7 cells transfected a ~ stable aon with vector p (TRE) 3-tk-Luc which places the expression of the gene for luciferase under the control of TPA (12-O-tetradécanoyl-phorbcl-13-acetate). TPA activates the AP-1 complex formed CA 0224329 ~ 1998-07-13 W 097/26237 PCT ~ R97 / 00079 _ 58 proteins from the nuclear protooncogen family (c-Jun and c-Fos). This MTLN line makes it possible to study the relationship between the estrogenic pathways and AP-1 (ME Astruc et al., Endocrinology, 19g5, 136, 824-832), and S to show the dissociation between transactivating activity and the anti-AP-1 effect of synthetic retinoids (JY Chen et al., EMBO J., 1995, 14, 1187-1197). The experiences are do with MTLN cells activated by TPA 10-7 M.
The results reported in Table 17 below below show that the 3 types of acid receptors retinoic expressed by MCF-7 cells (RAR ~, y and RXR ~) mediate an inhibitory effect on the AP-1 pathway. The use of the RAR ~ selective antagonist Ro 41-5253 does not allow completely remove the inhibition induced by TTNPB, which lS indicates that the activation of RAR ~ mediates an anti-AP-1 effect.
Activation by a RAR ~ agonist (Am580 10 nM) or RXRa (LGDl069 and LGD-CBl4499) also causes inhibition of the AP-l pathway. The association of a specific RAR molecule and a specific RXR molecule has a strong effect anti-AP-1 inhibitor, there is an additive effect between the two inhibition pathways. Due to its panagonist profile al ~ M, LGDl069 appears to be the most effective compound tested in this model.
Table 17 Product Concentration (Lo ~ M) Inhibition (%) ttRA -8 22 - 33 _7 28 - 44 9cisRA - ~ 0 - 37 Am580 - ~ 0 - 46 CB1449g The effect of the compounds on MTLN cells activated by TPA 10-7 M is expressed as a percentage. 100%

WO 97 / 2623'7 PCTAFR97 / 00079 represents the maximum activity level measured with the TPA
which is 5 to 6 times higher than the basal activity of cells. The inhibitory properties of the products are calculated after deduction of the basal activity of the cells.
The percentages reported correspond to a range of inhi ~ itions determined from several experiments.
Figure 2 in the appendix shows the additivity of ef ~ and anti-AP-1 inhibitor on the MTLN line of a RXR agonist and a selective RAR agonist.

6) Anti-estroqene effect of retinoids reference on activated estrogen-dependent cells by estradiol - T, igneous MELN.
MCF-7 cells express RARa, ~ and RXRa. The transfection of MCF-7 cells with an estrogen gene dependent (EP ~ E- ~ Glob-Luc) allowed to establish the line MELN cell, used to determine anti-estrogenic retinoids. These cells contain the luciferase gene under the transcriptional control of the promoter of ~ Globin and the ERE response element isolated from the chicken vitelogenin A2 gene. The experiments are carried out with activated MELN cells estradiol 10-9 M. The basal activity level of MELN cells is obtained with the antiestrogen 4-OH-tamoxi ~ ene (hydroxytamoxifen) 1 ~ M. This level is always 8 to 10 times lower than the maximum reference activity measured in the presence of estradiol 10-9 M which represents 100 ~.
ttRA reduces cell growth and expression of estrogen-dependent genes (E. Demirpence et al., Cancer Res.,] 994, 54, 1458-1464), what this MELN line allows to check well.
Selective RAR molecules (Am580 and TTNPB) induce an inhibition of the order of 40%. Am580 to one specific RARa concentration ~ 10 nM) allows inhibition maximum, which indicates that RARa mediates the effect CA 0224329 ~ 1998-07-13 WO 97/26237 PCTn ~ R97 / 00079 antiestrogenic in MCF-7 cells. The use of the antagonist RARa Ro 41-525 ~ lifts the inhibitory effect of Am580 but also TTNPB which, under these conditions, retains RAR ~ y activity and loses its RARa activity. Compounds Selective RXRs (LGDl069 and LGD-CBl4499) are inactive.
Activation of RXR is therefore not involved in inhibition of the estrogenic pathway by retinoids in MCF - 7 cells.
These results are reported in Table 18 below, they are perfectly correlated to experiences of estrogen-induced cell proliferation.
The association of a specific RAR agonist and an agonist Specific RXR does not allow an inhibitory effect to be observed greater than that exercised by the agonist RAR alone.
lS Table ~ 8 ~ FFET ANTI-- ESTROGENI ~ EU
Product Concentration (Loq M) Inhibi ~ on (9 ~) ttRA --7 - ' 9 - cisRA - ~
Am580 - 36--51 TTNPB - '30--LGDl069 --7 ~

The effect of the products tested on cells activated by estradiol 10 9 M is expressed as a percentage, the basal activity level being subtracted.
6) Conclusion.
The reference molecules made it possible to show ~
the efficiency and complementarity of the different models used and lead to the following conclusions:
- the chimeric constructions GAL-RAR and RAR-ERcassette allow to determine the RAR agonist profile molecules, but also RXR agonist activity with RAR-ERassette, WO 97126237 PCT ~ FR97 ~ 00079 - the HRLN line mainly translates the activity of a compound mediated by endogenous RARa, - the HRL + N line also highlights a retinoid agonist RXR activity, - the anti-estrogenic effect of retinoids (proli ~ estrogen-induced cell aeration and ME ~ N line) is mediated by RARa, - the anti-AP-1 effect is mediated in the cells MCF-7 (MTLN line) by RARa, RARy and RXRa, and an ef ~ and 1 () additive exists between the RAR and RXR channels.

B) Activity ~ of derivatives of the retinoid tv ~ e trans series (E).
The results obtained with the molecules of the series ~ E) are to be compared with ceu ~. presented for molecules of re ~ erence and for the molecule SRI3946 (CB241 ~ 9). This compound is selective RAR.

1) Specificity of the derivatives tested.
The RAR agonist activity of the series (E) was evaluated with the RAR-ERcassette model. To one concentration of 1 ~ M, the molecules of the invention of this series allow transactivation mediated by three types of RAR receptors. Their activity is reported in Table 19 below and, at this concentration, appears comparable to that of TTNPB.
Table 19 RAR-ER cassettes Product Concentration RARa RAR ~ RARr (Log M),%) (%) (%) TTN ~ - '~ 00 10 ~ 100 CB ~ 9 - ~ 13 11 89 CB ~ 4 - ~ 74 1 78 CB1 ~. - 90 1 '106 CB5. ~ 0- - t '73 1' 84 WO 97/26237 PCT ~ FR97 / 00079 _ 62 2) Effect of derivatives of the trans (E) series on the estroaeno-induced proliferation - MCF-7 cell liana and T-47D.
Table 20 below reports the effect of retinoids on the growth of MCF-7 and T-47D cells which is evaluated after 7 days of culture in the presence estradiol 10-9 M by assaying cellular DNA La molecule CB24159 inhibits the growth of T-47D cells dose dependent manner with efficacy greater than 10 that of TTNPB. CB73364 has an effect comparable to TTNPB. The other molecules induce an inhibition of around 50 ~ at the concentration of 0.3 ~ M which corresponds to their RAR ~ activity observed in specificity at this concentration (cf. RAR-ERcassette model).
15Table 20 ANTIPROLIFERATIVE EFFECT
ProductConcentration T-47D
(Loq M) CB24159 1.4 +/- 0.2 CB73364 4.1 +/- 0.7 CB71802 -6 72%
CB12273 252.8 +/-109.7 CB57201 233.0 +/-90.6 CB38973 -6 55%

3) Transactivating activity of trans derivatives (F) mediated by the receptors of retinoic acid HRLN cell lines.
As shown in Table 21 below, the structural modifications made to the molecules of the trans series (E) cause a decrease in effi ~ ciency important of these molecules in transactivation However, 2 ~ at ~ M, they allow an induction comparable to that TTNPB and CB24159. This activity matches the profile WO 97 / 2623'7 PCT ~ R97 ~ 00079 .

RAR of these molecules determined with the RAR- model ~ Rcassette.
Table 21 HRLN TRANSACTIVATION
Product E max% ECso (nM) TTNPB 1000.55 +/-, 072 CB24159 lC00.08 +/- 0.10 CB73364 8 '' 33 CB71802 7 ~ 31.4 +/- 16.9 CB12273 10621.4 ~ / - 5.6 BC ~ 7'01 7055.8 +/- 70.1 CB 0 60 10 638.3 +/- 9.5 CB_8973 8914.9 ~ / - 12.3 s 4) F. anti - estogenic effect of the trs ns derivatives (F.) on estrogen-dependent cells activated p ~ r estradiol - Ti ~ née MF.TN.
As shown in Table 22 below, the derivative CB241 ~ 9 is the most inhibitory compound for estrogenic transcription on the MELN model. His activity is perfectly correlated to its properties transcriptional mediated by RAR in the HRLN llgnée.
As for CB24159, the maximum inhibition provo ~ ued by lS trans molecules (E) is around 30 to ~ 0 ~. The effect anti-estrogenic retinoids being mediated by RARa in MCF-7 cells, these compounds exert their inhibition through this receiver, which corresponds to their RAR ~ mediated transcriptional power (cf. HRLN models and RARa-ERcassette).
Table 22 WO 97/26237 PCT ~ R97 / 00079 EFF: .T ANTI-ESTROGEN-QUE
Product Concentration Inhlbition (Loq M) C) Activities ~ es derived from the retinoid type of the invention of the cis (Z) series.
These derivatives are divided into two families:
- carboxylated molecules (substituting P ~
- molecules whose carboxyl is replaced with a tetrazole.

1) Specificity of cis derivatives (Z).
The two types of constructions (Gal-RAR and RAR-ERcassette) were used to highlight the interest of this series.

a) Gal4-RAR chimeric receptors 1 ~ The Gal-RAR constructions made it possible to assess RAR agonist activity of the cis (Z) series derivatives.
The results reported in Table 23 below show that the reference molecule SRI (CB28628) is complete agonist for the three types of RAR receptors and 2Q allows the same maximum transactivation as TTNPB (RAR

CA 02243295 l998-07-l3 Wo 97/26237 PCT / FR97 / 00079 selective agonist). The molecules derived from CB28628 appear less effective. Carboxylated molecules (CB364 ~ 3 and CB16279) are partial agonists at 1 ~ LM
for the three RAR receivers while CB38416 is Partial agonist for RARa and RAR, B, but complete for RARr.
These molecules have the property of inducing a RAR mediated transactivation Compounds with a tetrazole (CB92834 and CB77402) are unable to transactivate via RAR receptors. They don't are not RAR agonists.
Table 23 GAL-RAR
Product Concentration RAR ~ (~) RAR ~ (~ O) RAR ~
(Loq M) ~ TNPB -8 100 100 100 SRI (CB28628) -7 103 102 106 C ~ 38416 -6 58 51 99 CE, 36493 -6 38 44 50 C ~ 16,279 -6 33 47 59 C ~, 77402 -6 6 0 0 b) ER-cassette chimeric receptors As reported in Table 24 below, the pro ~ it defined with the RAR-ERcassette model for cis derivatives (Z) differs from the Gal-RAR profile. TTNPB 10 nM
exhibits the maximum transactivation induced by a selective RAR synthetic agonis_e. SRI (CB28628) is complete agonist for RARr-ERcassette and induces a over-activation of RAR ~ - ERcassette and RAR ~ B-ERcassette a 1 ~
This overactivation reflects panagonist properties (RXR and RAR agonist). Carboxylated compounds (CB30382, CB38416, CB36493 and CB16279) induce transactivation mediated by the three receptors. An over-activation of RAR, B-ERcassette intervenes with these molecules, which translates an RXR activity. The cis (Z) carboxylated derivatives are also W 097/26237 PCT ~ FR97 / 00079 panagonists. Molecules with a tetrazole (CB92834 and CB77402) do not allow transactivation mediated by RARa-ERcassette and RARy-ERcassette. However, a partial transactivation of RAR ~ -ERcassette is noted. Insofar as these compounds are inactive on Gal-RAR ~, this partial agonist effect can be attributed to an RXR activity. In addition, the combination of CB92834 or CB77402 with a specific RAR agonist allows a overactivation of the effect of the RAR molecule alone for three RAR-ER cassettes, which tends to confirm RXR agonist activity of CB92834 and CB77402 Table 29 RAR-ER cassettes Product Concentration RAR ~ (%) RAR ~ (~) RAR ~ (%) (Log M) SRI (CB28628) -7 95 115 87 '-8 1 0 0 2) F ~ ffet of the molecules of the cis (Z) series on the estrogen-induced proliferation - Cell lines MCF-7 and T-47D.
Table 25 below reports the effect of cis (Z) derivatives on the growth of T-47D cells which WO 97 / Z6237 PCT ~ FR97 ~ 00079 is evaluated after 7 days of culture in the presence estradiol 10-9 M by assaying cellular DNA. The carboxylated molecules induce order inhibition from 20 to 50% which corresponds to their RAR profile ~ agonist Partial S determined in transient transfections (Gal-RAR and RAR-ERcassette). SRI (CB28628) complete agonist, allows a inhibition on the order of 70 ~, comparable to that exerted by Am580. CB92834 is inactive on growth estrogen-induced.
Table 2 5 ConcentrationGrowth PRCDUIT (Log M) 100% = E2 10-9 M
SRI (CB28628) -6 33 CB ~ 6493 -6 68-78 CB ~ 8416 -6 50-60 3) Transactivating activity of cis derivatives (Z) mediated by retinoic acid receptors - ~ iqnées HRLN and HRL + N.

a) Tiqnée HRLN.
RAR agonist activity of cis derivatives (Z) carboxylated (CB38416, CB30382, CB36493 and CB16279) observed with the chimeric models is confirmed with the model HRLN, as reported in Table 26 below. At 1 ~ M, these compounds induce a transactivation close to that TTNPB. However, the structural changes effect ~ ées on these derivatives entail, compared to the reference SRI (CB28628) a decrease in affinity, and therefore RAR mediated efficacy. Compounds with a WO 97/26237 PCT ~ FR97 / 00079 -tetrazole (CB92834 and CB77402) are very weakly active, which corresponds to their activity in RAR-ERcassette.
Table 2 ~
TRI ~ NSACTlVA ~ LON HFULN
Pnoduct E max%
lrrNPB 100 SRI (CB28628) 98 CB ~ 2834 21 b) Li ~ née H ~ T + N.
The HRL + N line makes it possible to highlight a RXR agonist activity. The results reported in the table 27 below are correlated to those obtained with the RAR-ERcassette model. SRI (CB28628) is a molecule panagonist. It induces maximum transactivation higher than that of TTNPB. The compounds of the cis series (Z) carboxylated (CB38416, CB16279) appear as panagonists, in agreement with the results observed in RAR-ERcassette, and cause transactivation superior to selective RAR agonists (TTNPB). The non-cyclic CB (Z) molecules containing a tetrazole (CB92834, CB77402) allow to observe a low transactivation, lower than that of TTNPB. The association CB92834 or CB77402 with a specific RAR agonist induces a stronger transactivation than that observed for each compound tested separately, which corresponds to RXR agonist profile of CB92834 and CB77402.
Table 27 CA 0224329 ~ 1998-07-13 W 097126237 PCTAFR97 / 00 ~ 79 _ 69 HRL + N TRANSACTIVATION
Product E max%

Figure 3 in the appendix shows the over-activation by CB92834 of agonist-induced transactivation Selective RAR on the HRL + N line.

4) Anti-AP-1 Effect of the Ci. ~ Derivatives (Z) on TPA-activated estrogen-dependent cells - Lineage cell ~ TT, N.
The MTLN line activated by TPA allows to study the effect of the cis derivatives (Z) on the AP-1 pathway.
1 ~ Interpretation of the results reported in Table 28 below is based on the conclusions made from effects observed with re ~ erence molecules. The activations of RAR ~, RARy and RXRa mediate an anti-AP- effect l in MCF-7 cells and there is additivity of effects of RAR and RXR. CB28628 has a strong anti-AP-1 on MCF-7 cells. Like LGDl069, this molecule exerts a strong inhibition due to its properties panagonists. All molecules in the series (Z) have an AP-1 inhibitor profile. The carboxylated compounds (CB36493 and CB30382) at concentration l have an inhibitory effect comparable to that of the effect of CB28628. These panagonist derivatives (cf. results RAR-ERoassettes and HRL + N) induce an anti-AP-1 effect by activation of RAR and RXR receptors. CB92834 and CB77402 also have an inhibitory profile. Inhibition measured is around 20 to 30%, comparable to that noted for LGD1069 lO 8M (RXR selective at this concentration). CB92834 and CB77402 are anti-molecules WO 97/26237 PCT ~ R97100079 _ 70 AP-1 via RXR. In association with a selective RAR agonist, an anti-AP-1 effect is observed additive. These two compounds therefore have the advantage to transrepress the AP-1 pathway without inducing activation of the transcription of a gene controlled by a RARE.
Table 28 ProductConcentrationInhibition (Loq M) (~) Figure 9 shows the additivity of the effe ~
anti-AP-1 inhibitor on the MTLN line of CB77402 and Am580.
5) Anti-estrogenic effect ~ es cis derivatives (Z) lS on ~ es estrogen-dependent cells activated by estradiol - MELN line.
The use of reference molecules allowed to show that the anti-estrogenic effect of retinoids is mediated by RARa. The anti-estrogenic action of cis derivatives (Z) evaluated with the MELN line, activated by estradiol

10-9 M, follows their RARa profile. As reported in the Table 29 below, the carboxylated derivatives (CB36493, CB38416, CB30382 and CB16279), partially agonists, allow a transrepression of a gene controlled by a WO 97/26237 PCTfiFR97 ~ 007 _ 71 .

TIME. CB92834 and Cs77402 are inactive, which is perfect agreement with their inability to activate RAR ~.
Table 29 ANTI-ESTROGENIC EFFECT MELN
ProductConcentration Inhibition (Loq M) ~) ~ TNPB -8 30-41 SRI (CB28628) -7 31 CB303 ~ 2 -7 0 C ~ 92834 -6 0 6) Conclusion.
The derivatives of the invention of ser-e cis (Z) present very interesting properties. Compounds CB92 ~ 34 and CB7740 ~ have a specific RX ~ activity, compared to the carboxylated cis (Z) molecules which are panagonists (CB36493, CB30382, CB38416, CB16279). So the substitution of the carboxyl with a radical.
a loss of RAR activity and makes it possible to orient these molecules towards a specificity R ~ R. These compounds exert ~ n effect 1 ~ inhibitor on the AP-1 pathway and are inactive on the transcription of a gene controlled by a RARE. Their association with a specific RAR molecule allows optimize the anti-AP-1 effect of these molecules.

Other characteristics and advantages of the invention will appear on reading the examples which follow regarding preparation and analysis of compounds CA 0224329 ~ 1998-07-13 WO 97/26237 PCTA ~ R97 / 00079 of re ~ erence and derivatives of the invention, it being understood that these examples cannot be interpreted as tending to reduce the scope of the claims.
Example 1: Preparation of acid (E) 4 ~
(5.6,7,8-tetrahydro-3,5,5 8 3-pentamethyl-2-naphthalenyl) -2-propenyllbenzoic (CB71802) of formula:

a) Preparation of 2,5-dichloro- ~, 5-~ 0 dimethylhexane:
To a solution of 2,5-dimethyl-2,5-hexanediol (20.0 g, 136.8 mmol) in 250 ml of dichloromethane is added to the ambient thionyl chloride (25 ml, 341.8 mmol ~. The reaction medium turns yellow and we continue lS agitation for 4 h. The progress of the reaction is checked by thin layer chromatography (TLC) (eluent ether: petroleum ether = 5C: 50). At the end of the reaction, we addi ~ ionne 250 ml of distilled water, decant and phase organic is neutralized with 2 x 250 ml of a solution of NaHCO3 10%. It is then dried by MgSOq, filtered and evaporated at dry. 18.37 g are obtained (gross yield = 73%) of a solid the 2,5-dichloro-2,5-dimethylhexane.
1 H NMR 200 MHz (CDCl3): 1.57 ~ s, 12H, Me); 1.92 (s, 4H, -CH2-).
b) Preparation of l, 1,4 4 6.7-hexamethyl-1 2.3 4-tetrahydronaphthalene:
In a 250 ml three-necked flask fitted with a cooler, magnetic stirring and a thermometer, we weigh aluminum trichloride (3.0 g, 22.5 mmol). We add 70 ml o-xylene (Aldrich) then with a dropping funnel a solution of 2,5-dichloro-2,5- is added dimethylhexane prepared in the previous step (15.00 g, 81.9 WO 97/26237 PCT ~ FR97 / 00079 mmol) in 30 ml of o-xylene. The medium is heated to 100 ~ C
reactive for 3 h, there is an important ~ release of HCl and the reaction medium of ~ 7ient rou ~ e sombre ~ After cooling of the reaction medium, this is poured on a water-ice mixture (200 ml), extract with ether (3 x 80 ml), washed with a saturated solution of NaHCO3 (2 x 150 ml), dries the ethereal phase with MgSO4, filters and evaporates. The crude product is purified by vacuum distillation, 15.20 g of a solid are obtained 1,1,4,9,6,7-hexamethyl - 1,2,3,4 - tetrahydronaphthalene (Yd =
8696).
RMN1H 200MHz (CDC13): 1.31 (s, 12H, 1-Me and 4-Me); 1.71 (s, 4H, --CH2 -); 2.26 (s, 6H, 6 and 7 Me); 7.11 (s, 2H, ArH).
1 ~ c) Pre ~ aration of 6-bromomethyl-1 1.4 4 7-1,2,3,4-tetrahydronaphthalene pentamethyl of formula: =
A solution of 1,1,4,4,6,7-hexamethyl-1,2,3,9-tetrah ~ t ~ dronaphthalene (6.91 g, 31.9 mmol), from NBS (5.97 g, 33.5 mmol), benzoyl peroxide (0.22 g, 0.9 mmol) in 100 ml of CC14 is brought to reflux for 5 h. The solution is then cooled, concentrated on a rotary evaporator, reprlse with ether (100 ml), filtered to remove the succinimide ~ elm (succinimide being washed with ether) and concentrated. 8.80 g of a crude compound product are obtained (1 H NMR 200 MHz) of about 30 ~ 6 of 1,1,4,4,6,7-hexamethyl-1,2,3,4-tetrahydronaphthalene, about 65 ~ -O of 6-bromom ~ thyl-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene desired and about 5 96 of -compound matching dibroma. This gross product will be used as which for the ~ ormation of the corresponding phosphonium salt.
RMN1H 200MHz (CDC13): 1.27 (s, 12H, 5.8-CH3); 1.67 (s, 4H, 6.7-CH2-) i 2.36 (s, 3H, ArMe); 4.50 (s, 2H, BnzH); 7.05 (s, 1H, ArH ortho Me); 7.22 (s, 1H, ArH meta Me).

., -WO 97/26237 PCT ~ FR97 / 00079 d) Preparation of (5 ~ 6,7t8-tetrahydro-) bromide 3.5 5.8.8-pntamethyl-2-naphthalenyl) -methyl: ~
triphenylphosphonium of formula 6-bromomethyl-1,1,4,4,7-pentamethyl-1,2,3,4-S crude tetrahydronaphthalene (8.80 g, approx. 32 mmol) prepared previously is mixed with triphenylphosphine (10.1 g, 38.4 mmol) dissolved in 50 ml of dlchlorométhane during 24 h, then diluted with ether ethyl (200 ml). Bromide of ~ (5,6,7,8-tétrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) methyl]
triphenylphosphonium precipitates, is filtered and washed abundantly with ether. 10.72 g of crystals are obtained white, bromide (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -methyl-triphenylphosphonium (Yield = 60 ~) after drying.
1 H NMR 200 MHz (CDCl 3): 0.74 (s, 6H, 5-CH3); 1.15 (s, 6H, 8-CH3); 1.52 (broad s, 2H, 6-CH2) i 1.56 (broad s, 2H, 7-CH2);
1.56 (s, 3H, ArMe); 4.98 (d, 2H, -CH2-P J 16.8 Hz); 6.77 (s, 1H, ArH ~ 2.8Hz); 6.84 (s, 1H, ArH); 7.78-7.46 (m, 15H, ~ 0 ArH).
e) Pre ~ aration of (E) and (Z) 4- ~ 1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-: ~
propenyllbenzonitriles of formulas:
NC

CN

~ S (E) (Z) A solution of (5,6,7,8-tetrahydro-) bromide 3,5,5,8,8-pentamethyl-2-naphthalenyl) -methyl triphenylphosphonium (3.65 g, 6.5 mmol) prepared previously NaH (Aldrich, 6.0 mmol) from 0.24 g WO 97 / 2G23'7 PCT / FR97tO0079 of a dispersion of 60% NaH in oil in 5 ml of Anhydrous DMSO is stirred under argon for 30 min, then is added a solution of 4-cyanoacetophenone (1.45 g, 10.0 mmol) in 5.5 ml of DMSO. The solution is stirred for 6 h at room temperature then poured on ice (100 g). We then extracted with ether (5 x 100 ml). The gross product is puri ~ ed by flash chromatography on silica (eluent ether pure petroleum) then purified again by chromatography flash on silica (eluent ether: petroleum ether = 1:
99) in order to separate the isomers. 0.25 g of a white solid (Z) 4 - [- 1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] benzonitrile (Yield =
14g6) then 0.20 g of another white solid on (E ~ 4 - t - 1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] benzonitrile (Yield = 11%) and 0.18 g of a mixture of ~ x isomers (Yield c 10%).
Isomer (E):
1 H NMR 200 MHz (CDCl3): 1.28 (s, 12H, 5.8-CH3);
1.68 (s ~ 4H, 6.7-CH2-); 2.16 (d, 3H, vinyl Me J 0.8 Hz);
2.24 (s, 3H, ArMe); 6.91 (broad s, 1H, vinyl H); 7.13 (s, 1H, ArH); 7.16 (s, 1H, ArH); 7.62 (s, 2H, ArH meta at CN); 7.63 (s, 2H, ArH ortho to CN).
Isomer (Z):
1 H NMR 200 MHz (CDCl 3): 0.78 (s, 6H, 5-Me); 1.20 (s, 6 ~ 1, 5.8-Me); 1.40-1.60 (m, 4H, 6.7-CH2); 2.21 (d, 3H, Vlnylic J 1.5Hz); 2.25 (s, 3H, ArMe); 6.51 (s, 1H, ArH
); 6.59 (br s, 1H, vinyl H); 7.00 (s, 1H, ArH); 7.19 (d, 2H., ArH meta at CN J 8.4 Hz); 7.46 (d, 2H, ArH ortho to CN J 8.4 Hz).
f) Preparation of the acid (~) 4- ~ 1- (5.6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyllbenzoic acid (compound C ~ 71802) of formula:

CA 0224329 ~ 1998-07-13 W 097/26237 PCTnFR97 / 00079 ~ COOH

A suspension of the derivative ~ E) 4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] benzonitrile (0.22 g, 0.64 mmol) prepared previously dissolved in potash (0.94 g, 16.8 mmol) hydroethanolic (H2O 0.55 ml and EtOH 3.3 ml) is chau ~ fairy at 70 ~ C under magnetic ~ itation for 5 h.
The progress of the reaction is monitored by HPLC. After cooling of the reaction medium, it is taken up in water (50 ml), acidified with 1N HCl, extracted with ether (4 x 20 ml), dry the ethereal phase with MgSO4, filter and evaporate to obtain a crude product which is purified by washing with hexane. After drying at 50 ~ C (3 h) in a desiccator empty, 0.18 g (yield = 75%) of a solid is obtained whitish, acid (E) 4 - [- 1- (5,6,7,8-tetrah ~ dro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] benzoic pure.
F (~ C) = 209-210 (dec.).
1 H NMR 200 MHz (CDCI3): 1.29 (s, 12H, 5.8-CH3);
1.69 (s, 4H, 6.7-CH2); 2.19 (d, 3H, vinyl Me J l, 1Hz);
2.26 (s, 3H, ArMe); 6.95 (broad s, 1H, vinyl H); 7.13 (s, 1H, ArH); 7.19 (s, 1H, ArH); 7.63 (d, 2H, ArH meta at COOH J 8.4 Hz); 8.11 (d, 2H, ArH ortho to COOH J 8.4 Hz).
MS EI 70 eV (m / z,% intensity): 362 (M +, 79%) i 347 (M + -CH3, 100).
HRMS EI 70 eV: Mtr = 362.2220 for C25H30 ~ 2 Mth = 362.2246 HPLC: ODS column, Ultrasosphere, 5 ~, 250 x 4.6 mm, Shimadzu UV detector, 260 nm, flow rate 1 ml / min, eluent MeOH: H2O = 90: 10 + 0.1% TFA, acid (compound CB71802) tr CA 02243295 l998-07-l3 W 09 ~ J ~ 6 ~ 37 PCT ~ FR97 / 00079 _ 77 = 11.4 min 99.0%; impurities tr = 8.0 min 0.5% and tr = 9.0 min 0.3 ~.
IR (pure, cm 1): 3400-2500; 2958; 1688, 1604, 1420, 1288, 1186, 1124, 1066, 1016, 908, 850.

Example 2: Preparation of the acid (z) 4-rl-(5,6, 7,8-tetrahydro-3, 5,5,8,8-pentamethvl-2-naphthalenyl) -2-propenvllbenzo-ique ~ compound CB32706 ~ of formula:
HOOC ~

~ 1 ~ W

A suspension of the derivative (Z) 4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] benzonitrile (30 mg, 0.08 mmol) prepared previously, in potash (0.21 g, 3.84 mmol) hydroethanolic (H2O 0.11 ml and EtOH 0.7 ml) es ~ chau ~ fée 1 ~ at reflux with magnetic stirring for 6 h. We evaporate etXanol on a rotary evaporator, take up in water (20 ml), acidified with HC1 lN, extralt (5 x 40 ml) with ether, dry the pha, ethereal on MgSO4, filters and evaporates. The product is recrystallized from hexane, filtered and dried. We obtains 110 mg of a white solid, acid (Z) 4- [1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] benzoic (compound CB32706) (Yield = 95 ~).
F (~ C) = 185.
1 H NMR 200 MHz (CDCl 3): 0.76 (s, 6H, 2 Me); 1.20-(s, 6H ~ 2 Me); 1.40-1.60 ~ m, 4H, 2 -CH2-) i 2.23 (d, 3H, Me vinyl J 1.3 Hz); 2.25 (s, 3H, Me); 6.57 (s, 2H, ArH);
6.99 ("1H, vinyl H); 7.20-7.30 ~ m, 2H, ArH); 7.90 (d, 2H, ArlI, J 8Hz).

WO 97/26237 PCT ~ R97 / 00079 ~ 78 MS EI 70ev (m / z, ~ intensity): 362 (M, 69, S%);
347 (100); 149 (13).
HPLC: ODS column, Ultrasosphere, 5 ~, 250 x 4.6 mm, Shimadzu UV detector, 260 nm, flow rate 1 ml / min, eluent MeOH: H2O = 90:10 ~ 0.1 ~ TFA, flow rate 1 ml / min, acid (CB32706) tr = 12.1 min 99.2%.
IR (cm): 2926; 1688; 1606; 1418; 1280.

F. example 3: Preparation of (E) 5-r4- U- (5 6 7 8-tet ~ hydro-3 5 5.8 8-pentamethyl-2-naphthalenyl) -2-propenyllphenyll-1H-tetrazole (compound CB407 ~ 7) of formula N -N

To a solution of (E) and (Z) 4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamét ~ yl-2-naphthalenyl) -2-propenyl] benzonitriles prepared previously (0.32 g, 0.93 mmol) in anhydrous toluene (5 ml), add successively dibutyltin oxide (23 mg, 10% mol) and trimethylsilyl azide (0.247 ml, 1.86 mmol, 2 eq.). The reaction medium is heated for 16 h at reflux (110 ~ C) under an argon atmosphere and magnetic stirring. We precipitates with rectified chloroform to obtain after filtration 31 mg of a white solid on (E) 5- ~ 4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] phenyl ~ tetrazole (compound CB40747) pure after drying in a vacuum dryer (with P2Os).
F (~ C) = 256-258 (dec.).
1 H NMR 200 MHz (DMSO-D6): 1.24 (s, 12H, 5 and 8-Me); 1.64 (s, 4H, -CH2-); 2.15 (d, 3H, Me ~ 0.7 Hz); 2.21 (s, 3H, Me); 7.02 (s, 1H, vinyl H); 7.16 (s, 2H, ArH);
7.81 (d, 2H, ArH meta with tetrazyl ~ 8.4 Hz); 8.05 (d, 2H, WO 97126237 PCT / F1 ~ 97/00079 .

Ar ~ ortho to tetrazoyl ~ 8.4Hz). Peak H2O at 3.30; DMSC peak) 2.48.
MS EI 70 eV (m / z,% intensity): 386 (M +, 100%);
371 t29), 359 (21), 358 (71), 343 (25), 328 (11), 327 (19), 312 (1,).
HMRS EI 70 eV: Mtr = 386.2450 for C25H30N4 Mth =
386.2470.
HPLC: ODS column, Ultrasosphere, 5 ~, 250 x 4.6 mm, Shimadzu UV detector, 260 nm, eluent MeOH: H2O =
90:10 - ~ 0.1 ~ TFA, flow rate 1 ml / min, tetrazole (Cs40747) tr =
9.10 min 97.9 ~, impurity tr = 6.75 min 1.53%.

F. example 4: Preparation of (Z) S-r4-rl- (5 6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl ~ -2-propenvllphénvll-1H-tetrazole (compound CB61692) of formula N ~ ¦ ¦

I
H ~

To a solution of (Z) 4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] benzonitrile above (0.24 g, 0.70 mmol) in anhydrous toluene (1.4 ml), successively added dibutyltin oxide (22.3 mg, 0.09 mmol, 10 ~ mol) and trimethylsilyl azide (0.19 mi, 1.40 mmol) Le reaction medium is heated 23 h at reflux (110 ~ C) under argon atmosphere and magnetic agitation. After ~ 25 cooling of the reaction medium, the toluene and purifies the crude product by chromatography flash on silica (eluent dichloromethane: methanol = 90:
10). C) n obtains 0.30 g of a product which is dissolved in WO 97/26237 PCT ~ R97 / 00079 a minimum of chloroform and precipitates with hexane.
After filtration and washing with hexane then drying with desiccator, 0.18 g of a white solid is obtained, the ~ Z) 5-[4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] phenyl] -1H-tetrazole (CB61692) (Rdt = 66%).
F (~ C) = 210-1 H NMR 200 MHz (DMSO-D6): 0.68 (s, 6H, Me); 1.15 (s, 6H, Me); 1.30 (s, 4H, -CH2-); 2.23 (d, 6H, Me); 6.54 (s, 1H, ArH); 6.59 (br s, 1H, vinyl H); 7.31 (s, 1H, ArH); 7.35 (d, 2H, ArH meta with tetrazole ~ 8.2 Hz); 7.90 (d, 2H, ArH ortho to tetrazole J 8.2 Hz).
MS EI 70 eV (m / z, ~ intensity): 386 (M +, 100%);
371 (31), 359 (21), 358 (73), 343 (29), 328 (16), 327 (21), 1 ~ 312 (21).
HMRS EI 70 eV: Mtr = 386.2466 for C25H30N4 Mth =
386.2470.
HP ~ C: ODS column, ~ ultrasound, 5 ~, 250 x 4.6 mm, Shimadzu UV detector, 260 nm, flow rate 1 ml / min; eluting MeOH: H2O = 90:10 + 0.1% TFA, tetrazole (CB61692) tr = 8.8 min 98.1%, impurities tr = 8.0 min 0.3% and tr = 12.0 min 1.6%.

~ xem ~ 5 and 6: Preparation of acids (E) and ~ Z) 4-rl- (3 '4'-dihydro-4'4'-dimethyl-1',1'-dioxide-2'H-l'-henzothiQpyran-6'-yl) -2-propenyllbenzoic (compounds CB39356 and CB72484) of forms:
~ COOH
, ~, I, 15J
S

0 ~ ~ 0 (E) WO 97126237 PCT ~ P'R97 / 00079 HOOC

.,: ~ - ~

0 '~
(Z) a) Preparation of 3- ~ ethylbut-2-enyl-4'-hromopllenyl sulfide.
To a 60% sodium hydride solution in dispersion in mineral oil (3.2 g, 80 mmol) in 31 ml of anhydrous THF, added dropwise at temperature amblante a solution of 4-bromothiophenol (12.7 g, 61 mmol) in 18.5 ml of anhydrous THF. Leave to agitate at room temperature 30 min, then a solution of 1-bromo-3-methyl-but-2-ene (7.7 ml, 67 mmol) in 15.5 ml anhydrous THF and sodium iodide (1.83 g, 12 mmol).
The reaction medium is stirred at room temperature for 12 h. Hydrolyzed at 0 ~ C with 30 ml of water. After reto ~ r at room temperature, extract with ether (5 x 50 ml), dry over MgSO ~ and evaporate the solvents. We obtain 18.23 g of a yellowish oil, 3-methylbut-2-enyl-4'-bromophenylsulfide (gross yield = 100%).
1 H NMR 200 MHz (CDCl 3): 1.60 (s, 3H, Me); 1.70 (s, 3H, Me); 3.50 (d, 2H, -CH2- ~ 7.7Hz); 5.20-5.30 (m, 1H, H
vinyl); 7.13-7.24 (m, 2H, ArH); 7.33-7.39 (m, 2H, ArH).
b) Preparation of 6-bromo-4.4-dimethyl-3,4-~ ihydr ~ -2H-1-ben7Othiopyrane.
To a solution of 3-methylbut-2-enyl-4'-crude bromophenylsul ~ ure prepared in the previous step (18.23 g, 61 mmol) in 600 ml of dichloromethane, we have ~
-10 ~ C aluminum trichloride (8.9 g, 57 mmol). The ~ reaction medium is stirred at this temperature for 3 CA 0224329 ~ 1998-07-13 W 097/26237 PCTn ~ R97 / 00079 h, then poured over 500 ml of a volume water-ice mixture at volume. Extracted with dichloromethane and the organic phase is washed with a saturated aqueous NaHCO3 solution, then dried over MgSO4, filtered and evaporated. ~ e gross product is purified by flash chromatography on silica (eluent ether petroleum: ethyl ether = 100: 5. 12.62 g are obtained of an oil, 6-bromo-4,4-dimethyl-3,9-dihydro-2H-1-benzothiopyran (yield = 80%).
1 H NMR 200 MHz (CDCl 3): 1.30 (s, 6H, 2 Me); 1.80-2.00 (m, 2H, -CH2-); 2.80-3.05 (m, 2H, -CH2-S); 6.85-7.60 (m, 3H, ArH).
c) Preparation of ~ - ~ 3rmvl-4 4-dimethyl-3 4-dihydro-2H-1-benzothlopyrane.
Has magnesium (0.30 g, 12 mmol) in 1 ml of THF
anhydrous, 6-bromo-4,4-dimethyl-3,4- is added at 66 ~ C
dihydro-2H-1-benzothiopyran prepared in the previous step (b) (2.62 g, 10 mmol) dissolved in 5 ml of anhydrous THF.
Stirred at reflux of THF until almost consumption full of magnesium (30 min). The reaction medium is then cooled to -10 ~ C and added at this temperature from 1 to N - formy 1 morpho 1 ine (1.2 ml, 12 mmol) in 2 m 'of THF. At the end of the addition the reaction medium is brought to room temperature for 1 hour. After hydrolysis with 10 ml of a solution saturated aqueous NH4Cl at 0 ~ C and extraction with ether ethyl (5 x 30 ml), the organic phase is dried over MgSO4, filtered and evaporated. The crude product is purified by flash chromatography on sillce (eluent petroleum ether : ethyl ether: 100: 5). We get 2.00 g of 6-formyl-4,9-dimethyl-3,9-dihydro-2 ~ -1-benzothiopyran (Yd =
61%).
1 H NMR 200 MHz (CDCl 3): 1.60 (s, 6H, 2 Me); 1.90-2.00 (m, 2H, -CH2-); 3.00-3.10 (m, 2H, -CH2-S); 7.10-7.25 (m, 1H, ArH); 7.45-7.55 (m, 1H, ArH); 7.60 (m, 1H, Ar-H);
9.85 (s, 1H CHO).

d) Preparation of 6- (hydroxymethyl) -4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran.
To a solution of 6-formyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran previous (2.00 g, 9.7 mmol) in 20 ml of ethanol is added at 0 ° C borohydride sodium (NaBH4) (0.36 g, 9.7 mmol). Agitation is continued at this temperature 30 min. After evaporation of ethanol, take up in 100 ml of ethyl ether and acidifies with an aqueous 3N HCl solution to pH = 1.
Extracted with ether, dried over MgSO4, filtered and evaporated solvents. The crude product is purified by flash chromatography on silica (eluent petroleum ether : ethyl ether: 100: 10). 1.85 g of 6- (hydroxymethyl) -4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran (Yield = 92%).
1 H NMR 200 MHz (CDCl3): 1.30 (s, 6H, 2 Me); 1.90 - 1.96 (m, 2H, -CH2-); 2.97-3.03 (m, 2H, -CH2-S); 4.56 (s, 2H, BnzH); 6.96-7.07 (m, 2H, Arh); 7.23-7.33 (m, 1H, ArH).
e) Preparation of 6- (bromomethyl) -4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran.
To a solution 6- (hydroxymethyl) -4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran previous (1.85 g, 8.9 mmol) in 6.2 ml of anhydrous toluene, added dropwise drop, with a syringe between 20 and 25 ° C of the tribromide phosphorus, (1 ml, 10.7 mmol.) Allow to stir room temperature 1 h. Hydrolyzed at 0 ° C with ice then with water, extraction is carried out with ethyl ether, dries on MgSO4 filters and evaporates the solvents. We obtain 2.14 g of 6- (bromomethyl) -4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran (gross yield - 88%).
1 H NMR 200 MHz (CDCl3): 1.30 (s, 6H, 2 Me);
1.89-1.95 (m, 2H, -CH2-); 2.97-3.03 (m, 2H, -CH2-S); 4.44 (s, 2H, BnzH; 7.03 (s, 2H, ArH); 7.33 (s, 1H, ArH).
f) Preparation of (4,4-dimethyl-3,4- bromide) dihydro-2H-1-benzothiopyranyl-6-methyltriphenylphosphonium.

CA 0224329 ~ 1998-07-13 W 097/26237 PCT ~ FR97 / 00079 6- (bromomethyl) -4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran from the previous step (2.14 g, 7.8 mmol) is mixed at room temperature with triphenylphosphine (2.52g, 9.6 mmol) dissolved in 7 ml dichloromethane for 18 h, then diluted with ether ethyl (50 ml). (4,4-Dimethyl-3,4-dihydro- bromide 2H-1-benzothiOpyranyl-6-methyltriphenylphosphonium precipitates, is filtered and washed thoroughly with ether. We obtains 4.36 g of white crystals which are dried with desiccator and used as is (gross yield = 100%).
1 H NMR 200 MHz (CDC13): 1.00 (s, 6H, 2 Me); 1.76--1.82 (m, 2H, -CH2-); 2.89-2.95 (m, 2H, -CH2-S); 5.23 (d, 2H, BnzH, J 14Hz); 6.60-6.70 (m, 1H, ArH); 6.80-6, ~ -5 (m, 1H, ArH); 7.15 (m, 1H, ArH); 7.55-7.85 ~ m, 15H, -PPh3).
ct) Preparation of (E) and (Z) 4- ~ 1- (3 ', 4' -dihydro-4 ', 4'-dimethyl-2'H-l'-ben ~ othiopyran-6'-yl) -2-propenyllbenzonitriles of respective formulas:
1 ''': ~

(E) (Z) A solution of (4,4-dimethyl-3,4-) bromide dihydro-2H-1-benzothiopyranyl) -6-methyltriphenyl phosphonium from the previous step (2.41 g, 4.5 mmol), NaH (Aldrich, 4.1 mmol) from 0.16 g of a dispersion of 6096 NaH in oil in 2.5 ml of DMSO
anhydrous is stirred under argon for 20 minutes, then is added a solution of 4-cyanoacetophenone (0.54 g, 3.75 mmol) in 5 ml of DMSO. The solution is stirred for 24 h at room temperature then poured on ice (70 g). We then extracted with ether (5 x 50 ml). The gross product is WO 97/26237 PCT ~ FR97 / 00079 _ 85 then purified by flash chromatography on silica (eluent petroleum ether: ethyl ether ether = 100: 10). We 0.24 g of a pure solid is obtained, (E) 4- [1- (3 ', 4'-dihydro-4 ', 4'-dimethyl-2'H-1'-benzothiopyran-6'-yl ~ -2-propenyl] benzonitrile (Yield = 20%) and 0.13 g of a solid, the (Z) ~ - [1- (3 ', 4'-dihydro-4', 4'-dimethyl-2'H-1'-benzothiopyran-6'-yl) -2-propen-yll benzonitrile (Yd

11%).
Isomer (E):
1 H NMR 200 MHz (CDCl 3): 1.33 (s, 6H, 2 Me); 1.93-1.99 (mf 2H, -CH2-); 2.26 (s, 3H, vinyl Me); 3.03-3.06 (m, 2H, -CH2-S); 6.83 (s, 1H, vinyl H); 7.07 (m, 2H, ArH); 6.78-6.87 (m, 2H, ArH); 7.33 (s, 1H, ArH); 7.50-7.70 (m, 2 ~, ArH).
lS Isomer (Z):
1 H NMR 200 MHz (CDCI 3): 1.10 (s, 6H, 2 Me); 1.56-1.86 (m, 2H, -CH2-); 2.16 (sr 3H, vinyl Me); 2.90-2.96 (m, 2H, -CH2-S); 6.46 (s, 1H, vinyl H); 6.60 (dd, 1H, ArH J 1.9Hz J 8, 1Hz); 6.78-6.87 (m, 2H, ArH); 7.28 (dd, 2H, ArH J 1.8 Hz, 3 6.8 Hz); 7.54 (dd, 2H, ArH J 1.8Hz J 6.8Hz).
h) Preparation of (E) 4 ~ (3 ', 4'-dihydro-4', 4 dimethyl-1 ', 1'-dioxide-2'H-l'-benzothiopyran-6'-yl) -2-pro ~ é'nyllbenzonitrile of formula:
~ CN

::: I J-TL ~
o ~ ~ o To a solution of (E) 4- [1- (3 ', 4'-dihydro-4', 4'-dimethyl-2'H-1'-benzothiopyran-6'-yl) -2-propenyl]
previous benzonitrile (0.24 g, 0.75 mmol) in 7 ml of - chloro ~ elm, add metachloroperbenzoic acid to 70-75 ~ (0.37 g, 1.5 mmol) at 0 ~ C. The agitation is continued at this temperature 2 h 30 The reaction medium is diluted with 15 ml of chloroform then washed with a solution _ CA 0224329 ~ 1998-07-13 aqueous Na2CO3 at 5 ~ (3 x 5ml). The organi ~ ue phase is dried over MgSO4, filtered and then evaporated. 0.25 g is obtained of a solid, the (E) 4- [1- (3 ', 4'-dihydro-1', 1'-dioxide-4 ', 4'-dimethyl-2'H-1'-benzothiopyran-6'-yl) -2-propenyl] benzonitrile (gross yield = 96%).
1 H NMR 200 MHz (CDCI 3): 1.41 (s, 6H, 2 Me); 2.23 (s, 3H, vinyl Me); 2.37-2.45 (m, 2H, -CH2-); 3.36-3.42 (m, 2H, CH2-S); 6.85 (s, 1H, vinyl H); 7.24-7.38 (m, 2H, ArH); 7.56--7.67 (m, 4H, ArH); 7.90 (d, 1H, ArH J 8, lHz).
I0 i) ~ repair of (Z) 4- ~ 1- (3'.4'-dihydro-4 '4'-dimethyl-1 '1'-dioxide-2'H-1'-benzothiopvran-6'-yl) -2-propenyll benzonitrile of formula:
NC ~

~ 1, To a solution of (Z) 4- [1- (3 ', 4'-dihydro-4', 4'-dimethyl-2'H-1'-benzothiopyran-6'-yl) -2-propenyl ~ -benzonitrile (0.21 g, 0.65 mmol) in 6.1 ml of chloroform, metachloroperbenzoic acid is added to 70-75% (0.32 g, 1.3 mmol) at 0 ~ C. Agitation is followed at this temperature for 3 h. The reaction medium is diluted with 15 ml of chloroform and then washed with a solution aqueous Na2CO3 at 5 ~ (3 x 5ml). The organic phase is dried over MgSO4, filtered and then evaporated. 0.21 g is obtained of a solid, (Z) 4- [1- (3 ', 4'-dihydro-4', 4'-dimethyl-1 ', 1'-dioxide-2'H-1'-benzothiopyran-6'-yl) -2-propenyl] benzonitrile (gross yield = 95 ~).
1 H NMR 200 MHz (CDCl 3): 0.95 (s, 6H, 2 Me); 2.15 (s, 3H, vinyl Me); 2.20-2.30 (m, 2H, -CH2-); 3.25-3.35 (m, 2H, CH2-S); 6.50 (s, 1H, vinyl H); 6.75 (s, 1H, ArH); 7.00 (dd, 1H, ArH J 1.3 Hz, J 1.3 Hz); 7.20 (m, 2H, WO 97/26237 PCT ~ nR97 / 00079 _ 87 .

ArH); 7.55 (d, 2H, J 7.5 Hz, ArH); 7.5 (d, 1H, J 7.5 Hz, ArH).
j) Preparation of the acid (E) 4-rl- (3 '4'-dihydro-4 ', 4'-dimethyl-1'.1'-dioxide-2'H-1'-benzothiopyran-6'-vl) -2-pro ~ enyll ~ enzoï ~ eu ~ compound CB39356) and 11acid (Z) 4-rl-(3 ', 4'-dihydro-4'i4'-dimethyl-1'1'-dioxvde-2'~-1'-benzothiopvran-6'-yl) -2-propenyllbenzoic (compound CB7248 ~) of the following respective formulas:
~ ,,,, COOH
~ l S (E) O ~ ~ O

HOOC ~

~ 1 (O
~ S ~
0 ~ 0 lQ A suspension of the mixture of (E) and (Z) 4- [1-(3 ', 4'-dihydro-4', 4'-dimethyl-1 ', 1'-dioxide-2'H-1'-benzothiopyran-6'-yl) -2-propenyl] benzonitriles (0.39 g, 0.75 mmol) dissolved in potash (0.5 g, 9.0 mmol) hydroethanolic (H2O 0.25 ml and EtOH 1.6 ml) is heated at reflux with magnetic stirring for 5 h. We evaporate ethanol on a rotary evaporator, take up in water (50 ml), acidifies with 3N HCl, extract (3 x 25ml) with ether, dries it ethereal phase on MgSO4, filter and evaporate. The gross product is purified by preparative HPLC on a Waters HR column Cl8 (25 x 100 mm) with CH3CN as eluent: H2O = 100:

CA 0224329 ~ 1998-07-13 WO 97/26237 PCTnFR97 / 00079 100 ~ 0.1 ~~ of TFA. 15.8 mg of a white solid are obtained, acid (E) 9- [1- (3 ', 4'-dihydro-4', 4'-dimethyl-l ', 1'-2-dioxide-~ -l'-benzo-thiopyran-6'-yl) -2-propenyl] benzoic (Yield = 6 ~) (compound CB39356) and 17.2 mg of a white solid, acid (Z) 4- [1- (3 ', 4'-dihydro-4', 4'-dimethyl-l ', l'-dioxide-2'H-l'-benzo-thiopyran-6'-yl) -2-propenyl ~ benzoic (compound CB72484) (Yield = 6%) Acid (E) 4- [l- (3 ', 4'-dihydro-4', 4'-dimethyl-, 1'-dioxide-2'H-l'-benzothiopyran-6'-yl) -2-propenyl]
benzoic (composes CB3g356):
F (~ C) = 270-274.
1 H NMR 200 MHz (CDCl3): 1.35 (s, 6H, 2 Me); 2.19 (d, 3H, Me vinyl J 1, OHz); 2.31-2.37 (m, 2H, -CH2-) i 3.30-3.36 (m, 2H, CH2-S); 6.80 (s, 1H, vinyl H); 7.30 (m, 2H, ArH); 7.49 (d, 2H, ArH J 8.3 Hz); 7.82 (d, 1H, ArH J
8, 1Hz); 7.97 (d, 2H, ArH J 8.3 Hz).
MS EI 70 ev (m / z, ~ intensity): 370 (M, 100%);
338 (30); 337 (43) i 44 (74) i 4 ~ (45) -MSHR FI 70 ev: Mtr = 370.1257 for C21H22O4S Mth = 370.1239.
HPLC: Waters HR Clg column, 8 x 100 mm, 6 ~, Waters 486 ~ UV detector at 300 nm, flow rate 2.5 ml / min, elua ~ t CH3CN: H2O = 50: 50 ~ 0.1% TFA, acid (compound CB39356) tr = 4.52 min 98.8 ~.
Acid (Z) 4- [1- (3 ', 4'-dihydro-4', 4'-dimethyl-, 1'-dioxide-2 '~ -1'-benzothiopyran-6'-yl) -2-propenyl]
benzoic ~ compound CB72484):
F (~ C) = 210.
1 H NMR 200 MHz (CDCl3): 1.02 (s, 6H, 2 Me); 2.20 (d, 3H, Me vinylic J 1.4 Hz); 2.23-2.27 (m, 2H, -CH2-) i 3.25-3.31 (m, 2H, CH2-S); 6.52 (s, 1H, vinyl H); 6.82 (d, 1H, ArH 3 1.3 Hz); 7.03 (dd, 1H, ArH J 8.3 Hz J 1.4 Hz);
7.24 (d, 2H, ArH J 7.9 Hz); 7.67 (d, 1H, ArH J 1.3 Hz); 8.03 (d, 2H, ArH J 8.3Hz).
MS EI 70 ev (m / z,% intensity): 37Q (M, 100%);
338 (10); 337 (44) - t WO 97/26237 PCTnFR97 / 00079 8g MSHR EI 70 ev: Mtr = 370.1265 for C21H22 ~ 4S Mth 370.1239.
HPLC: Waters HR C1 8 column, 8 x 100 mm, 6 ~, Uv waters 486 detector at 260 nm, flow 2.5 ml / min, eluent CH3CN: H2O = 50: 50 + 0.1% TFA, acid (compound CB72484) tr = 5.51 min 97.89 ;.

Example 7: Preparation of (Z) 5-r4- ~ 1- (3'.4'-dihydro-4 '4'-dimethyl-1'1'-dioxide-2'H-1'-benzothiopyran-6 '- yl) - 2 - propenyllphenyl - 1H-tetrazQle (compound CB3912 ~) from following formula:
N ~ N
NOT
H
Jl 0 ~ ~ 0 To a solution of (Z) 4- [1- (3 ', 4'-dihydro-4', 4'-dimethyl-l ', 1'-dioxide-2'H-1'-benzothiopyran-6'-yl) -2-propenyl] benzonitrile (0.31 g, 0.90 mmol) in toluene anhydrous is added successively dibutyltin (30 mg, 0.11 mmol) and azide trimethylsilyl (0.24 ml, 1.80 mmol). The reaction medium is heated for 15 h at reflux (110 ~ C) under an argon atmosphere and magnetic stirring. Purify by chromatography flash on silica (eluent CH2Cl2: MeOH = 95: 5) for obtain 0.16 g of a solid, the (Z) 5- [9- [l- (3 ', 4'-dihydro-9 ', 4'-dimethyl-1', 1'-dioxide-2'H-1'-benzothiopyran-6'-yl) -2 - propenyl] phenyl] -1H-tetrazole ~ compound CB39122) (Yield =
46%).
F (C) = 94.

WO 97/26237 PCT ~ R97 / 00079 9 (1 1 H NMR 200 MHz (CDCl 3): 1.05 (s, 6H, 2 Me); 2.24 (s, 5H, vinyl Me and -CH2-); 3.25 (m, 2H); 6.50 (s, 1H, H vinyl); 6.91-6.98 (m, 2H, ArH); 7.23-7.27 (m, 2H, ArH); 7.62 (d, 1H, ArH J 8Hz); 7.98 (d, 2H, ArH J 8Hz).
S MS EI 70 ev (m / z, ~ intensity): 394 (M, 42.9%);
354 (59); 321 (61); 293 (69); 44 (100).
MSHR EI 70 ev Mth = 394.1464 for C21H22N4O2S;
~ Mtr = 394.1489.
HPLC: Waters HR Clg column, 8 x 100 mm, 6 ~, Waters 486 UV detector at 26Q nm, 2.5 ml / min, eluent MeOH: H2O = 75: 25 + 0.1 ~ of TFA, sulfone (CB39122) tr = 4.6 min 97 ~ 5 ~ O; impurities tr = 4.3 1.9 ~; tr = 5.7 0.5%.

lS F.xemDle 8: Preparation of the (E) 5- ~ 4- ~ 1- (3 ', 4'-~ ihydro-4 '4'- ~ imethyl-1'1'-dioxide-2'H-l'-henzothiopyran-6'-yl) -2-propenyllphenyl-1H-tet ~ zole (compound CB15068) of following formula:
NN

OO
To a solution of (E) 4- [1- (3 ', 4'-dihydro-4', 4'-dimeth.yl-l ', l'-dioxide-2'H-1'-benzothiopyran-6'-yl) -2-propenyl] benzonitrile (0.31 g, 0.75 mmol) in toluene anhydrous, successively add oxide of dibutyltin (22.4 mg, 0.09 mmol) and azide trimethylsilyl (0.20 ml, 1.5 mmol). The reaction medium is heated for 15 h at reflux (110 ~ C) under an argon atmosphere and magnetic stirring. Purified by preparative HPLC
on a Waters HR C1g column (25 x 10Q mm) with as eluting MeOH: H2O = 75: 25 + 0.1 ~ of TFA to obtain CA 02243295 l998-07-l3 WO 97126Z3 ~ 7 PCT / F'R97 / 00079 .

after evaporation and drying in a desiccator 50 mg of a white solid, (E) 5- [4- [1- (3 ', 4'-dihydro-4', 4'-dimethyl-1 ', 1'- ~ dioxide-2'H-1'-benzothiopyran-6'-yl) -2-propenyl] phenyl] -1H-tetrazole (compound CB150 ~ 8) (Yield =
17%) -F (~ C) = 224.
1 H NMR 200 MHz (DMSO-d6): 1.38 (s, 6 ~, 2 Me); 2.47 (s, 5H, -CH2- and Me vinyl); 3.30-3.45 (m, 1H, -CH2-S);
3.50-3.60 (m, 1 ~, -CH2-S); 7.12 (s, 1H, vinyl H); 7.53 (d, 2H, ArH J 8.5HZ); 7.65 (s, 1H, ArH); 7.76-7.87 (m, 3H, ArH); 8.07 (d, 1H, ArH J 8.5Hz).
MS EI 70 ev (m / z, ~ intensity): 394 (M, 100%);
351 (4,); 321 (38), 293 (39).
MSHR EI 70 e ~: Mtr = 394.1449 for C21H22N402S
1 ~ Mth = 394.1464.
HPLC: Waters HR C1g column, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 2.5 ml / min, eluent MeOH: H2O = 75: 25 + 0.1% TFA (CB15068) tr =
2.2 min 100 ~.
~ xample 9: Preparation of (E) 4 ~ (5 6 7 8-tetrahydro-5 5 8 8-tetramethyl-2-naphthalenyl) -2-propenyll-N- (tetrazol-5-yl) -ben ~ amide (compound CB73369) of formula next :
. , ~ JH

a) Preparation of 1 1 4 4 6-pentameth'yl-1 2.3 4-tetrah ~ ydronaphthalene.
i) In a 250 ml three-necked flask fitted with a refrigerant, magnetic stirring and thermometer, weigh aluminum trichloride (3.0 g, WO 97126237 PCT ~ FR97100079 _ 92 -22.5 mmol). 70 ml of anhydrous toluene are added (distilled and dried with a 4A molecular sieve) then, by bromial bulb, add a solution of 2.5-2,5-dichloro-dimethylhexane (15.00 g, 81.9 mmol) in 30 ml i, anhydrous benzene. The medium is heated to 10C ~ C
reaction for 2 h. There is a significant release of HCl and the reaction medium becomes dark red. After cooling of the reaction medium, this is poured on a water-ice mixture (200 ml), extraction is carried out with ether (3 x 80 ml), washed with a saturated solution of NaHCO3 (2 x 150 ml), dries the ethereal phase with MgSOg, filters and evaporates. the raw product is purified by vacuum distillation, 12.76 g (yield = 779 ~) of 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene [Eb (~ C) ~ ';, = 66-67 under 1.5 mrnHg].
1 H NMR 80 MHz (CDCl3): 1.20 (s, 12H, 1.4-Me); 1.60 (s, 4H, -CH2-); 2.25 (s, 3H, 6-Me); 6.80-7.30 (m, 3H, ArH).
ii) To a distilled toluene solution (20.0 g, 217.0 mmol) and 2,2,5,5-tetramethyltetrahydrofuran (Aldrich, 12.5 g, 97.5 mmol) is added at 0 ~ C by small fraction of anhydrous AlC13 (Aldrich, 13.3g, 100 mmol). The cold bath is then removed and the medium reaction stirred for 72 h. We then add 10 ml of a 3N HCl solution, separates the organic phase and extract the aqueous phase with ether (3 x 75 ml). We combines the organic phases, washed with a solution saturated with NaHCO3, dried over MgSOq, filtered and evaporated. The crude product obtained is distilled under vacuum, 12.2 is obtained g (yield = 62%) of an oil 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene cold crystallizing.
1 H NMR 80 MHz (CDCl3): 1.20 (s, 12H, 1.4-Me); 1.60 (s, 4H, -CH2 -); 2.25 (s, 3H, 6-Me); 6.80-7.30 (m, 3H, ArH).
b) Pre ~ arat ion of 6 - bromomé thy 1 -1,1,4,4, 1,2-tetramethyl 3 4- ~ etrahydxonaphthalene 3 ;, A solution of 1, 1,4,4,6-pentamethyl-1,1,4,4-tetrahydronaphthalene (2.14 g, 60.0 mmol), 2 ~ BS (11.21 g, W 097/26237 PCTn ~ R97 / 00079 63.0 mmol), benzoyl peroxide (0.436 g, 1.80 mmol) in 120 ml of CC14 is brought to reflux for 1 h. The solution is then re ~ roidie, diluted with ether petroleum (120 ml), filtered and concentrated giving an oil S yellowish. Distill (128-134 ~ C, 1.2 mmHg) to obtain 9.24 g of a colorless oil, 6-bromomethyl-1,1,4, ~ -l, tétraméthyl-1,2,3,4-tétrahydro- naphtalène ~ Yield =
55%) -1 H NMR 80 MHz (CDCl3): 1.25 (s, 12H, Me); 1.65 (s, 4H, --CE12 -); 4.40 (s, 2H, BnzH); 7.2-7.0 (m, 3H, ArH).
c) Pre-paid brom ~ re of (5,6,7,8-tétrahydro-5.5 8.8-tetramethyl-2-naphthalenyl) methyl- tri ~ hényl-phosphonium.
6-bromomethyl-1,1,4,4, tetramethyl-1,2,3,4-tetrahydronaphthalene (9.0 g, 32.0 mmol) prepared in step previous is mixed with triphenylphosphine (10.1 g, 38.4 mmol) dissolved in 50 ml of dichloromethane for 24 h, then diluted with ethyl ether (200 ml). (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- bromide 2-naphthalenyl) rnethyltriphenylphosphonium precipIte, is filtered and washed with ether. White crystals obtained 15.0 g (yield = 86%) are dried in a desiccator.
F (~ C) = 270-271.
1 H NMR 200 ~ Hz (CDC13): 0.54 and 0.88 (2s, 12H, 5.8-Me); 1.53 (s, 4H, 6.7-CH2-); 5.13 (d, 1H, -CH2P J 14 Hz); 6.88-6.75 ~ m, 2H, 1- and 3-ArH ~; 7.02 (d, 1H, 4-ArH J 8 Hz); 7.8-7.5 (m, 15H, -PPh3).
d) Preparation of (E) and (Z) 4- ~ 5 6 7 8-tee ~ rahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyll benzonitriles of formulas res ~ ectlves:

CA 02243295 l998-07-l3 W097 / 26237 PCTn ~ 7/00079 Cl'1 CN ~

'~', - T 'Z' A bromide solution of (5,6,7,8-t ~ etrah-ydro-5,5,8,8-tetramethyl-2-naphthalenyl) methyltriphenyl-phosphonium (6.25 g, 11.5 mmol), NaH (10.5 mmol), from 0.42 g of a 60 ~ 6 dispersion of NaH in the oil, in 35 ml of anhydrous DMSO is stirred under argon for 20 min, time to which a solution is added of 4-cyanoacetophenone (1.45 g, 10.0 mmol) in 15 ml of DMSO. The solution is stirred for 6 h at ambient then poured over ice (150 g). Then extracted with ether (125 ml, 3 x 50 ml). The crude product is then purified by three successive flash chromatographies on silica (1 ~
eluent hexane: acetone = 5: 95, 2 ~ eluent hexane acetone = 4: 96.3 ~ eluent hexane: acetone = 2.5: 97.5) in order to separate the (E) and (Z) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl ~ -benzonitriles. To obtain the pure (Z) isomer (minus polar as the isomer (E)), we check the different ~ HPLC reactions. The (Z) isomer can be recrystallized in hexane. The (E) isomer crystallizes in the fractions from flash chromatography, it is filtered, washed at WO 971Z6Z37 PCT ~ 97 ~ 00079 hexane and dried with a vane pump, its purity is determined by HPLC analysis.
0.57 g of (E) 4- r 1- is obtained (5,6,7,8-tetrahy ~ ro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl ~
benzonitrile in the form of a white solid (pure yield =
17.5 ~) and 0.96 g of (Z) 4- [1- ~ 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] benzonitrile under ~ elm of a white solid (Yield = 30 ~). We also get 0.70 g of a mixture of the two isomers (Yield mixture = 18%).
Isomer lE):
F (~ C) = 173.
200MHz H NMR (CDCl3): 1.29 (2s, 12H, 5.8-CH3);
1.69 (s, 4H, 6.7-CH2-); 2.29 (d, 3H, vinyl Me J 1.3 Hz);
6.87 (5 broad, 1H, vinyl H); 7.13 (dd, 1H, 3-ArH J
8Hz, J 1.9Hz); 7.28 (m, 1H, 1-ArH); 7.31 (d, 1H, 9-ArH J
8.4Hz); 7.60 (m, 4H, ArH ortho and meta at CN).
HPLC: Lichrosorb L5-25F column, 5 ~, 250 Y. 4.6 mm; eluent EtOAc: hexane = 5: 95.
flow rate: 1 ml / min, detection ~ V at 260 nm; isomer (E) tr = 6.25 min 98.8%
Isomer (Z):
F (~ C) = 126-H NMR 200MHz (CDC13): 0, g5 and 1.19 (2s, 12H, 5.8-CH3); 1.57 (s, 4H, 6.7-CH2-1i 2.16 (d, 3H, Me vinylic J
1.2Hz); 6.49 (d, 1H, vinyl H J 1.2 Hz); 6.72 (m, 1H, 3-ArH); 6.73 (s, 1H, 1-ArH); 7.07 (d, 1H, 4-ArH J 8.6 Hz);
7.30 (cl, 2H, ArH meta at CN J 8Hz) i 7.56 (d, 2H, ArH ortho at CN J 8Hz).
HPLC column Lichrosorb ~ 5-25F, 5 ~, 250 ~ 4.6 mm; eluent AcOEt: hexane = 5: 95 flow rate: 1 ml / min, UV detection at 260 nm, Isomer (Z) tr = 6.8 min 98.3%, isomeric impurity (E) tr = 6.29 min 1.1%.
f) Preparation of the acid (E) 4- r 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethvl-2-naphthalenyl) -2-propenyll benzoic formula:

g6 ~ COOH

A suspension of (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] benzonitrile (0.44 g, 1.20 mmol) dissolved in potash (Q, 94 g, 16.8 mmol) hydroethanolic (H2O 0.55 ml and ~ tOH 3.3 ml) is heated to reflux under magnetic agltation for 4 h. The progress of the reaction is monitored by CCM (eluent acetone: hexane = 10:90). The ethanol is evaporated at the rotary evaporator, takes up in water (50 mI), acidifies with 1N HCl, extracted 3 times with ether, drying the phase ethereal with MgSO4, filters and evaporates to obtain after washing with pentane and drying 0.40 g of a white powder, acid (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] benzoic (Yd = 96 ~).
1 ~ F (~ C): 230-2.
H NMR 200MHz (CDC13): 1.29 and 1.30 (2s, 12H, 5.8-CH3), 1.69 ~ s, 4H, 6.7-CH3); 2.32 (s, 3H, vinyl Me);
6.91 (s, 1H, vinyl H); 7.16 (d, 1H, 3-ArH J 8Hz), 7.29 (s, 1H, 1-ArH); 7.31 (d, 1H, 4-ArH J 7.9 Hz); 7.60 ~ d, 2H, ArH meta at COOH J 8.4 Hz); 7.60 (d, 2H, ArH orto at COOH J
8.4Hz).
HPLC: ODS Ultrasound Column, 5 ~, 250 x 4.6 mm, UV detection at 260 nm, eluent MeOH: H2O = 90:10 + 0.1%
TFA, pressure about 2500 psi, acid ~ r = 12.7 min 99.9 ~, impurity tr = 9.1 min 0.1 ~.
IR (pure, cm-1): 3400-2200, 2928, 1672, 1602, 1424, 1280 MicroanalySe C24H28 ~ 2:
Tr.% C 82.06% H 7.95 =
Calc. ~ C 82.72% H 8.10 WO 97 / 2623'7 PCT ~ R97100079 _ 97 MS ~ I 70 ev (m / z): 3 ~ 8 (M +, 75%); 333 (M + - CH3, 100).
g) Pre ~? ~ ration du (F.) 4 ~ t5.6,7.8-tétrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyll -N-(tetraz ~ l-5-yl ~ -benzamide (compound CB73364) of formula ~ uiv ~ nte:

~ ~ I N-- ~ N

To an acid solution (E) 4- [1- (5,6,7,8-tetrahyclro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl]
benzoic acid (0.10 g, 0.29 mmol) in 5 ml of anhydrous THF is additio ~ born at room temperature 1 equivalent of N, N'-carbonyldiimidazole (Aldrich, 0.46 g, 0.29 mmol). A half hour later we add the equivalent of 5-aminotetrazole monohydrate (Aldrich, 0.30 g, 0.29 mmol).
The magnetic stirring is continued for 3:30 p.m., a white precipitate in the reaction medium has formed. We evaporates to dryness and adds 10 ml of 1N HCl, filters the solution, wash with water and methanol the ~ iltrat, we obtained after drying overnight in a desiccator (with P2Os) 15 mg of a white solid, the (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -N- (tetrazol-5-yl) benzamide (CB73364) ~ Yd = 12 ~).
F (~ C) = 318-321.
1 H NMR 200 MHz (DMSO D6): 1.24 (s, 12H, 5.8-CH3);
1.64 (s, 4H, 6.7-CH2-) i 2.27 (d, 3H, vinyl Me); 7.03 (s large, 1H, vinyl); 7.15-7.45 ~ m, 3H, ArH); 7.75 (d, - 2H, ArH meta at COOH ~ 8.4Hz); 8.11 (d, 2H, ArH ortho to COOH ~ 3.4Hz). H2O signal at 3.58, DMSO signal 2.49.
MS DIC (isobutane) 200 eV (m / z,% intensity): 416 (M ++ 1.100%); 172 (22), 154 (48).

WO 97/26237 PCT ~ R97 / 00079 F ~ example 10: Preparation of (E) 5- ~ 4 ~ (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyll phenyll-1H-tetrazole (compound CB62458) of fo ~ mule:
NN

To a solution of E) 4- [1- (5,6,7,8-tetrar. ~ Dro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] benzonitrile (0.24 g, 0.73 mmol) in anhydrous toluene (1.25 ml), successively add dibu oxide ~ ylétain (15,1 mg, 10% mol) and 2 equivalents of trimethylsilyl azide (0.19 ml, 1.46 mmol). The reaction medium is heated 16 h at reflux (110 ~ C) under an argon atmosphere and agitated ~ ion magnetic. Purified by chromatography flashed on silica (eluent CH2C12 then MeOH: CH2C12 = 5:95) for obtain after evaporation, 0.13 g of a powder ~ lanche, the (E) 5- [4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- ~
naphthalenyl) -2-propenyl ~ phenyl] -1H-tetrazole (CB62458) (Rdt = 48%) -F (~ C) = 224-225.
1 H NMR 200 MHz (CDC13 + DMSO D6): 1.02 and 1.03 (2s, 12H, 5.8-CH3); 1.43 (s, 4H, 6.7-CH3); 2.08 (d, 3H, Me J
lHz); 6.63 (broad s, 1H, vinyl H); 6.85-7.10 (m, 3H, ArH), 7.40 (d, 2H, ArH meta of tetrazoyl J 8.4 Hz); 7.81 (d, 2H, ArH ortho to tetrazoyl ~ 8.4Hz).
MS EI 70 ev (m / z,% intensity): 372 (M +, 100%); 357 (28); 344 (74); 329 (31); 313 (23) 298 (13).
MSHR EI 70 ev: Mtr = 372.2312 for C24H28N4 Mth = 372.2314 HPLC: ODS column, Ultrasosphere, 5 ~, 250 ~ 4.6 mm, Shimadzu UV detector, 260 nm, eluent MeOH: H2O =

WO 97/26237 PCT ~ R97 / 00079 .

90:10 + 0.1% TFA, tetrazole (CB62458) tr = 11.5 min 99; 4%, tetrazole impurity (CB92834) tr = 8.5 min 0.5%

F. Example 11: Preparation of ~ (Z) 5- r4- ~ l- (5,6,7,8-S tetrahydro-5 S 8 8-tetramethyl-2-naphthalenyl) -2-propenyll p ~ enyll-1H-tetrazole (compound CB92834) of ~ ormule:

N ~ N
NOT
H

To a solution of (Z) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] benzonitrile (1.20 g, 3.64 mmol) in anhydrous toluene (6.25 ml), successively add dibutyltin oxide ~ 75 mg, 10% mol) and trimethylsilyl azide (0.97 ml, 7.28 mmol). The reaction medium is heated for 16 h at reflux (110 ~ C) under argon atmosphere and magnetic stirring. Qn purifies by flash chromatography on silica (eluent CH2C12 then MeOH: CH2C12 = 5: 95) to obtain after evaporation, washing with hexane and drying with a vane pump, 0.99 g of a white powder, the (Z) 5- ~ 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] phenyl] -lH-tetrazole (CB92834) (YId = 73%).
F (~ C) = 191-3.
RMN1H 200MHz (CDC13): 0.91 and 1.19 (2s, 12H, 5.8-CH3); 1.50 (s, 4H, 6.7-CH3); 2, lS (d, 3H, Me vinylic J
1.2Hz), 6.46 (broad s, 1H, vinyl H); 6.72 (dd, 1H, 3-- 25 ArH J ~ ', 3Hz J 1.5Hz), 6.82 (d, 1H, 1-ArH J 1.6Hz); 7.01 (d, 1H, 4- ~ rH J 8.2Hz); 7.32 (d, 2H, ArH meta of tetrazoyl J
8, 1Hz), 8.03 (d, 2H, ArH ortho of tetrazoyl J 8, 1Hz).

WO 97/26237 PCTn ~ R97 / 00079 13 C NMR 50 MHz (CDCl3): 26.7; 31.3; 31.6; 33.8;
33.9; 34.8; 122.3; 126.0; 127.4; 127.6; 127.9; ~ 129.3;
133.7; 136.0; 143.2; 144.1; 148.2.
MS EI 70 ev (m / z,% intensity): 372 = (M +, 100%); 357 (M + -CH3, 20); 344 (70); 329 (23); 313 (17).
MSHR EI 70 ev: Mtr = 372.2332 for C24H28N4 Mth = 372.2314.
HPLC: ODS column, Ultrasosphere, 5 ~, 250 x 4.6 mm, Shimadzu UV detector, 260 nm, eluent MeOH: H2O =
90:10 + 0.1 ~ TFA, tetrazole (CB92834) tr = 8.25 min 98.5 ~, tetrazole impurity (CB62458) tr = 11.2 min 1.5 ~.

Example 12: Preparation of the acid (E) 4- U-trifluoromethyl-2- (5 6 7 8-tetrahydro-5.5 8 8-tetramethyl lS -2-n ~ phthalenyl) -l-ethenyll benzoï ~ eu (compound CB364 ~ 3) of formula :
HOOC ~

~ CF3 , - "

a) Preparation of 1- (4-benzonitrile) -2,2,2-trifluoroeth ~ nol.
A solution of 4-cyanobenzaldehyde (Aldrich, 1.48 g, 11.28 mmol) and (trifluoromethyl) trimethylsilane (Fluka, 2 ml, 13.53 mmol) in 12 ml of THF is cooled to 0 ~ C then a catalytic amount of fluoride is added of tetrabutylammonium TBAF 1M in THF (0.1 ml, 0.1 mmol). Instantly the solution turns pale yellow and the solution is brought to room temperature for 4 h. We follows the reaction by thin layer chromatography. We hydrolysis at the end of the reaction with 1N HCl, add water then extracted with ether (150 ml), dried over MgSO4t W ~ 97J2623'7 PCT ~ FR97 / 00079 filter and evaporate to obtain 2.15 g of a solid, the 1- (4-benzonitrile) -2,2,2-trifluoroethanol (gross yield = 95 ~).
1 H NMR 200 MHz (CDC13): -3.56 (broad s, 1 H mobile, -OH); 5.08 (q, 1H, BnzH ~ 6.4Hz ~; 7.55-7.70 (m, 4H, ArH).
S RMN19F 100MHz (CDC13): - 78.64 (d, 3F, J 2.9Hz).
IR (pure, cm-1): 3384, 2242, 1616, 1506, 1410, ~ 1348, 1260, 1130 b) 1- (4-benzonitrile) -2.2 2-trifluoroethane-1 1-diol.
The mixture is refluxed for 24 h, with stirring strong magnetic and argon atmosphere, a solution 1- (4-benzonitrile) -2,2,2-trlfluoroét ~ anol (2.15 g, 10.7 mmol) and PCC (3.45 g, 16.0 mmol) in 150 ml of dichloromethane. At the end of the reaction, the medium is cooled reaction, filter on florisil (Et2O) where a crude product containing the expected diol mixed with about 15 ~ starting alcohol (detection by gas chromatography). We purify this mixture by flash chromatography on sillce (eluent Et2O: ether of petroleum = 20: 80) to obtain a first fraction containing 0.70 g of a mixture of alcohol and diol then a second fraction containing 1.40 g of a white solid the of 1- (4-benzonitrile) -2,2,2-trifluoroethane-1,1-diol (Yield =
60%).
IR (pure, cm): 3240 (wide), 2246, 1504, 1406, 1248, 1154, 1056, 1018, 922.
c) Prepaxation of 4- (cyano) - ~ a, ~ -trifluoroacetophenone.
In a 100 ml flask fitted with a Dean-Stark, magnetic stirring, a solution is brought to reflux 1- (4-benzonitrile) -2,2,2-trifluoroethane-1,1-diol (1,36 g, 6.26 mmol) in toluene (50 ml) for 3 h. We evaporates to dryness after cooling of the reaction medium, 3 ~ 1.25 g of 4- (cyano) -a, ~, ~ -trifluoroacetophenone are obtained (Gross yield = 100%).

CA 0224329 ~ l998-07-l3 WO 97t26237 PCT ~ FR97 / 00079 _ 102 -F (~ C) = 105 IR (pure, cm ~ 2232, 1724, 1606, 1410, 1148, 938, 856.
d) Preparation of (E) 4-rl-trifluorGmethyl-2-(5, ~, 7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-ethenyllbenzonitrile of formula:
CN
~ 1 1 ~ ", CF3 rl A solution of (5,6,7,8-tetrahydro-) bromide 5,5,8,8-tetramethyl-2-naphthalenyl) methyl triphenylphosphonium (4.28 g, 7.87 mmol), NaH (Aldrlch, 7.18 mmol) from 0.29 g of a dispersion of 60% NaH in oil in 25 ml anhydrous DMSO is stirred under argon for 20 minutes, duration to which a solution of 4- (cyano) is added -~, ~, ~ -trifluoroacetophenone (1.25 g, 6.26 mmol) in 10 ml from DMSO. The solution is stirred for 5 h at ambient then poured over ice (100 g). Then extracted with ether (3 x 50 ml). The crude product is then purified by flash chromatography on silica (eluent Et2O: ether of oil = 1:99). Each fraction is analyzed by HPLC to check that there is only one isomer and that the purity is sufficient. 1.35 g of a solid are obtained (E) 4- [1-trifluoromethyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-ethenyl ~ benzonitrile (Yield = 55 ~) that one recrystallizes from hexane to obtain 1.10 g of pure solid (Recrystallized yield = 46%). 0.08 g of (Z) 4- [1-trifluoromethyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-ethenyl ~ benzonitrile (Yield = 4%) that one recrystallizes from hexane to obtain 0.04 g (Yield recrystall.
= 2 ~

CA 02243295 l998-07-l3 WO 97/26237 PCT ~ FR97 ~ 0079 Isomer (E):
F (~ C) = 131-132 1 H NMR 200 MHz (CDC13): 0.96 and 1.19 (2s, 12H, 5.8-CH3); 1.58 (s, 4H, 6.7-CH2); 6.49 (dd, 1H, 3-ArH J
1.8Hz J 8.3 ~ z); 6.77 (d, 1H, 1-ArH J 1.8Hz ~; 7.13 (d, 1H, 4- ~ rH J 8.3H ~); 7.23 (d, 1H, vinyl H ~ 1.8Hz); 7.44 (d, 2H, ArH meta at CN J 8.2 Hz); 7.70 (d, 2H, ArH ortho at CN J
8.2Hz).
RMN19F 100MHz (CDC13): -65.6 (s, 3F, -CF3).
HPLC: Lichrosorb L5-25F column, 5 ~, 250 x 4.6 mm; eluent AcOEt: hexane = 3: 97, flow rate: 1 mlJmin, UV detection at 260 nm; isomer ~ E) tr = 6.6 min 99.8 ~.
Isomer (Z):
1 H NMR 200 MHz (CDCl 3): 1.29 (s, 12 H, 5.8-CH ~);
1.69 (s, 4H, 6.7-CHz); 7.05 (br s, 1H, vinyl H);
7.19 ~ dd, 1H, 3-ArH J 8Hz, J 1.9Hz); 7.32 (d, 1H, 4-ArH J
8Hz); 7.38 (d, 1H, 1-ArH J 1.9Hz); 7.56 (d, 2H, ArH meta of CN J 8.2 Hz); 7.68 (d, 2H, ArH ortho from CN J 8.2 Hz).
RMN19F 1QOMHz (CDC13): -56.6 ~ s, 3F, -CF3).
HPLC: Lichrosorb L5-25F column, 5 ~, 25û x 4.6 mm; eluent AcOEt: hexane = 3: 97, flow rate: 1 ml / min, UV detection at 26 nm; isomer (Z) tr = 12.6 min 95.2%, isomer (E) tr = 6.6 min 3.5 ~).
e) Preparation of the acid (E) 4- ~ 1-tr; fluoromethyl-2- (5,6 7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthalenyl) -1-ethenyllbenzQïaue (compound CB36493) of formula :
HOOC

~ =

CA 0224329 ~ l998-07-l3 WO 97/26237 PCTA ~ R97 / 00079 _ 104 .

A suspension of the derivative (E) 4- [1-trifluoromethyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthalenyl) -1-ethenyl] benzonit'rile (0.50 g, l, 30 mmol) in solution in potash (0.94 g, 16.8 mmol) hydroethanolic (H2O 0.55 ml and EtOH 3.3 ml) is heated at reflux with magnetic stirring for 5 h.
The progress of the reaction is followed by CCM. We evaporate ethanol in a rotary evaporator, takes up in water (50 ml), acidified with 1N HCl, extract (3 x 60 ml) with ether, dried the ethereal phase with MgSO4, filters and evaporates to obtain a crude product which is purified by flash chromatography on silica (eluent Et2O: petroleum ether 50:50, height silica = 5 cm). After evaporation of the fractions, we obtains a clear orange solid which is washed with pentane (x 2). After filtration and drying at 50 ~ C (24 h) at vacuum desiccator, 0.19 g of a solid is obtained blanchatre, acid (E) 9- [1-trifluoromethyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-ethenyl] benzoic (compound CB36493) pure (yield = 36%).
F (~ C): 161-162 (pentane) 1 H NMR 200MHz (CDCl3): 0.96 and 1.19 (2s, 12H, 5.8-CH3); 1.57 (s, 4H, 6.7-CH2-); 6.77 (dd, 1H, 3-ArH J
1.8Hz J 8.2Hz) i 6.88 (d, 1H, 1-ArH ~ 1.8Hz); 7.11 (d, 1H, 4-ArH ~ 8.2Hz) i 7.21 (d, 1H, vinyl H J 1.6Hz); 7.46 ~ d, 2H, ArH meta of COOH J 8.2 Hz); 8.16 (d, 2H, ArH ortho du COOH ~ 8.2Hz).
RMN19F 100MHz (CDCl3): -65.7 (s, 3F, -CF3).
MS EI 70 eV (m / z,% intensity): 402 (M ~, 51%);
387 (M + -CH3, 100 ~; 345 (16).
HRMS EI 70 eV: Mtr 402.1815 for C24H2sF3O2 Mtr 402.1807.
HPLC: ODS column, Ultrasosphere, 5 ~, 250 x 4.6 mm, Shimadzu UV detector, 260 nm, flow rate 1 ml / mln, eluent MeOH: H2O = 90: 10 + 0.1 ~ TFA acid (CB36493) tr = 7.63 min 99.5%; impurities tr = 6.41 min 0.15%; tr = 4.4 min 0.08%.

WO 97) 26237 PCT ~ 97 ~ 00079 _ 105 .

IR (pure, cm l): 2958, 1692, 1608, 1416, 1 ~ 84, ,, 1160, 1105, 922, 858.

Example 13: Preparation of (F.) 5- ~ 4- ~ 1-S trl fluoromethyl-2- (5, 6.7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-n ~ pht: alenyl) -l-ethenyll ~ hény ~ l-1H-tetra ~ ole (compound CB77402 ~ of formula:
~ N -N

H ~

~ 1 To a solution of (E) 4- [1-trifluoromethyl-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -l-ethenyl] benzonitrile (0.2 ~ g, 0.61 mmol) in toluene anhydrous (1.25 ml), successively add oxide dibutyltin (15.1 mg, 10 ~ mol) and azide trimethylsilyl (0.16 ml, 1.22 mmol). The reaction medium is heated at reflux for 16 h (110 ~ C) under an argon atmosphere and magnetic stirring. Purify by chromatography flash on silica (eluent CH2C12 then MeOH: CH2C12 = 5:
95) to obtain after evaporation then washing with pentane 0.15 g of a greenish powder, the (E) 5- [4- [1-trifluoromethyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-ethenyl] phenyl] -1H-tetrazole (CB77402) (Yield = 58 ~), which is dried at 50 ~ C (24h) in a desiccator.
This solid can be recrystallized with chloroform.
F (~ C) = 210-211.
- 2 ~ RMN1H 200MHz (CDCl3): 0.94 and 1.16 ~ 2s, 12H, 5.8-CH3); 1.54 (s, 4H, 6.7-CH2-); 6r 77 (dd, 1H, 3-ArHJ
1.7Hz J 8.2Hz); 6.93 (d, 1H, 1-ArH J 1.7 Hz); 7.09 td, 1H, 4-ArH J 8.2Hz) i 7.21 (d, 1H, vinyl H J 1.4Hz); 7.50 (d, CA 02243295 l998-07-l3 WO 97t26237 PCTn ~ R97 / 00079 _ 106 2H, ArH meta of tetrazoyl J 8.2 Hz); 8.17 (d, 2H, ArH ortho tetrazoyl ~ 8.2Hz ~.
RMN19F 100MHz (CDCl3): - 65.76 (s, 3F, -CF3).
MS EI 70 eV (m / z,% intensity): 426 (M +, 100%);
411 (M + -CH3, 74); 398 (80); 383 (35); 368 (15); 352 (16);
341 (11); 326 (10).
HRMS EI 70 eV: Mtr 426,2005 for C24H25F3N4 Mth 426.2031 HPLC: ODS column, Ultrasosphere, 5 ~, 250 x 4.6 mm, Shimadzu UV detector, 260 nm, flow rate 1 ml / mln, eluent MeOH: H2O = 90: 10 + 0.1 ~ TFA, tetrazole (CB77402) tr =
6.11 min 98.5% impurities: acid (CB36493) tr = 7.57 min l, 1 ~; unknown tr = 12.07 min 0.15 ~.

Example 14: Pre ~ aration of the acid (E) 4-rl-trifluorome ~ hyl-2- (5,6 7,8-tetrahydro-3 5 5,8,8-pentamethyl -2-naphthalenyl) -1-benzoic ethenyl (CB62899) of formula:
HOOC ~

~ <~

a) Preparation of (E) 4rl- ~ 5,6,7,8-tetrahydxo-3 5,5,8,8-pentamethyl-2-naphthalenyl) -2- (trifluoromethyl) -ethen-2-yl) lbenzonitrile ~ e formula:
CN ~

~ CF3 WO 97/26237 PCTMFR97 / 00079 _ 107 In a 50 ml flask fitted with a stirrer magnetic and under an argon atmosphere we introduced (5,6,7,8-tetrahydro - 3,5,5,8,8-pentamethyl-2- bromide naphthalenyl) methyltriphenylphosphonium (1.75 g, 3.14 mmol) dissolved in 10 ml of anhydrous THF. We add to -78 ~ C, drop by drop, a solution of tBuOK lM in the THF (3.26 ml, 3.26 mmol) and continues stirring at -70 ~ C
for 2 h. A solution of 9- is added to the syringe (cyano) - ~, ~, a-trifluoroacetophenone (0.50 g, 2.51 mmol) in 2.5 m ~ of THF. We continue the agitation and leave return to room temperature for 4 h 30 min.
hydrolysis at 0 ~ C with a 6N HCl solution (7 ml) then add 15 ml of distilled water before extracting dichloromethane (3 x S0 ml). We dry on MgSO4, filter and evaporates the solvents. The crude product is then puri ~ ié by flash chromatography on silica (eluent ethyl ether:
petroleum ether = 1.5: 98.5). 0.65 g of a white solid, (E) 4- [1-trifluoromethyl-2- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -1-ét ~ enyllbenzonitrile of formula:
CN ~

~ CF3 ~ ' (Yield = 65 ~) then 0.01 g of (Z) 4- [1-trifluoromethyl-2- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -1-ethenyl] benzonitrile (Yield =
1%).
_ Isomer (E):
F (~ C) = 89-90.
1 H NMR 200MHz (CDC13): 0.76 and 1.21 (2s, 12H, 5.8-CH3); 1.40-1.65 (m, 4H, 6.7-CH2); 2.32 (s, 3H, Me);

W 097/26237 PCTn ~ R97 / 00079 .

6, S4 (s, 1H, ArH); 7.06 (s, 1H, vinyl H); 7.36 (d, 2H, ArH); 7.45 (m, 1H, ArH ~; 7.60 (d, 2H, ArH). ~
RMN19F 100MH2 (CDC13): - 65.0 (S, 3F, --CF3).
Isomer (Z):
1 H NMR 200MH ~ (Cl:) C13): 1.26 (d, 12H, Me .D 1.6Hz) i 1.67 (s, 4H, 6.7-CH2); 2.27 (S, 3H, Me); 7.11 (s, 1H, ArH);
7.13 (s, 1H, ArH); 7.25 (s, 1H, vinyl H); 7.58 (d, 2H, ArH meta at CN J 8.4 Hz); 7.70 (d, 2H, ArH ortho at CN J
8.4Hz).
RMN19F 100MHz (CDC13): --56.8 (s, 3F, --CF3).
b) Preparation of the acid (E) 4- rl-~ trifluorQmethyl-2- (5 ~ 6 ~ 7 ~ 8-tetrahydrQ-3 ~ 5 ~ s ~ 8 ~ 8- ~? ent ~ methyl --2-naph ~ alenyl) -1-ethenyllbenzoic (compound CB62899 ~ from formula:
HOOC ~

~ .CF3 A suspension of the derivative (E) 4- [1-tri: Eluoromethyl-2- (5,6,7,8-tetrahydro-3,5,5,8,8-penta-methyl-2-naphthalenyl) -1-ethenyl] benzonitrile (0.56 g, 1.41 mmol) in solution in potaSSe (2.00 g, 35.71 mmol) hydroethanolic (H2O 6, 6 ml and EtOH 1 ml) is heated to reflux with magnetic stirring for 5 h. Advancement of the reaction is monitored by CCM. The ethanol is evaporated at the rotary evaporator, take up in water (50 ml), acidify with 1N HCl, extract (3 x 80 ml) with ether, dry the phase ethereal on MgSO4, filter and evaporate to obtain a crude product which is purified by flash chromatography on silica (eluent ether: petroleum ether = 70:30).
After evaporation of the fractions, 0.44 g of a white solid, acid (E) 4- [1-tri ~ luoromethyl-2- (5,6,7,8-WO 97/2623 ~, 7 PCTA ~ R97 / 00079 _ 109 .

tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -1-ethenyl] benzoic (CB62899) pure (yield = 75%).
F (~ C) = 151 (Kofler bench).
1H NMR 200MHz (CDCl3): 0.73 and 1.19 (2s, 12H, 5.8-CH3); 1.40-1.60 (m, 4H, 6.7-CH2-); 2.32 (s, 3H, Me);
6.60 (s, 1H, ArH); 7.04 (s, 1H, ArH); 7.37 (d, 2H, ArH
8.2Hz); 7.42 (s, 1H, vinyl H); 8.06 (d, 2H, ArH J
8.2Hz).
RMN19F 100MHz (CDCl3): -65.1 (s, 3F, -CF3).
MS EI 70 eV (m / z,% intensity): 416 (Mt, 47%);
401 (M + -CH3, 10Q); 359 (11).
HRMS EI 70 ev: Mtr 416.1962 for C2sH27F3O2 Mtr 416.1963.
HPLC: ODS column, Ultrasosphere, 5 ~, 250 x 4.6 lS mm, Shimadzu UV detector, 260 nm, flow rate 1 ml / min, eluent MeOH: H2O = 90: 10 + 0.1 ~ acid TFA (CB62899) tr = 9.5 min 97%; impurity tr = 11.2 min 2.65%.

~ xample 15: Preparation of (F) 5-r4-rl-trifluoromethyl-2- (5,6,7 8-tetrahydro-3,5,5,8.8-pentamethyl-2-naphthalenylt-l-ethenyllphenyl-1H-tetrazole (compound CB63237) of ~ ormule:

N ~ DN
NOT
H ¦ l ~ CF3 =
To a solution of (E) 4- [1-tri ~ luoromethyl-2-- 25 (5,6,7, .8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -l-ethenyl] benzonitrile (0.24 g, 0.60 mmol) in toluene anhydrous (1.25 ml), successively add oxide dibutyltin (15.1 mg, 10% mol) and azide WO ~ 7/26237 PCT ~ R97 / W079 trimethylsilyl (0.16 ml, 1.22 mmol). The reaction medium is heated at reflux for 16 h (110 ~ C) under an argon atmosphere and magnetic stirring. We could ~ ifie by chromatography flash on silica (eluent CH2Cl2 then MeOH: CH2C12 = 5:
95) to obtain after evaporation then washing with pentane and drying 0.13 g of a white solid, the (E) 5- [4- [1-trifluoromethyl-2- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -1-ethenyl] phenyl] -1H-tetrazole (CB63237) (Yield = 49%).
F (~ C) = 203-205.
1 H NMR 200 MHz (DMSO): 0.73 and 1.19 (2s, 12H, 5.8-CH3); 1.40-1.65 (s, 4H, 6.7-CH2-) i 2.34 (s, 3 ~, Me); 6.69 (s, 1H, ArH) i 7.12 (s, 1H, ArH) i 7.46 (d, 2H, ArH J 8.4Hz);
7.54 (s, 1H, vinyl H); 8.02 (d, 2H, ArH ~ 8.4Hz).
RMN19F 100MHz (CDC13). - 67.9 (s, 3F, -CF3 ~.
MS EI 70 eV (m / z, ~ intensity): 440 (M +, 90%);
425 (M + -CH3, 100); 412 (31); 397 T29) i 365 (10); 198 (12).
HRMS EI 70 eV: Mtr = 440.2178 for C25H27F3N4 Mth = 440.2169.
HPLC: ODS column, Ultrasosphere, 5 ~, 250 x 4.6 mm, Shimadzu UV detector, 260 nm, flow rate 1 ml / min, eluent MeOH: H2O = 90: 10 + 0.1 ~ TFA, tetrazole (CB63237) tr =
7.60 min 97.7 ~ impurities tr = 8.9 min 1.9%.

Example 16: Preparation of (E) ~ l- (5 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyllbenzene (compound CB04854) with the following formula:

~ J ~
a) Pre ~ aration of 1,1 4 4-tetramethyl-1 2 3,4-tetrahy ~ ronaphthalene.

CA 0224329 ~ 1998-07-13 WO 9712623 ~ T rCT ~ F R97J00079 .

In a 100 ml three-necked flask fitted with a condenser, magnetic stirring and a thermometer, we weigh aluminum trichloride (0.60 g, 4, ~ 9 mmol). We add 20 ml of anhydrous benzene then, using a dropping funnel, ~ ~ adds a solution of 2,5-dichloro-2,5-dimethylhexane (3.00 ~, 16.38 mmol) in 10 ml of anhydrous benzene. We reflux the reaction medium for 4 h. There is significant release of HCl and the reaction medium turns dark red. After cooling of the medium reaction, it is poured onto a water-ice mixture (100 ml). Extracted with ether (3 x 50 ml), washed with a saturated NaHCO3 solution (2 x 100 ml), dries the phase ethereal with MgSO4, filters and evaporates. The gross product is puri ~ ed by flash chromatography on silica (eluent ether petroleum). 1.95 g are obtained (yield = 63 ~) of a liquid colorless, 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene.
Eb (~ C) = 74 under 0.5 mmHg.
RM ~ 1H 200 MHz (CDC13): 1.28 (s, 12H, 1.4-Me); 1.68 (s, 4H, --CH2 -); 7.05--7.40 (m, 4H, ArH).
b) Preparation of 4- chloride chloride bromophenylac ~ tvle.
To a solution of 4-bromophenylacetic acid (Aldrich, 5 g, 23.2 mmol) in 10 ml of toluene is added to amionizing temperature thionyl chloride (2.5 ml, 34.8 mmol). The reaction medium is brought to reflux for 2 h. After returning to ambient temperature, the toluene and 5.55 g of 4- chloride are obtained crude bromophenylacetyl (crude yield = 100%).
c) Preparation of 9-rl- (5,6,7,8-tetrahydro-5.5 8,8-tetramethyl-2-naphthalenyl) -1-oxo-2-ethyllbromo benzene of formula;

WO 97/26237 PCTA ~ R97 / 00079 .

~ Br L 1 ~

To a solution of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.36 g, 23.2 mmol) in 300 ml of dichloromethane are added successively at -30 ~ C from S aluminum trichloride (4.33 g, 32.5 mmol) and chloride 4-bromophenylacetyl t5.55 g, 23.2 mmol). We let go back to 0 ~ C in 30 min, pour the reaction medium onto 400 ml of a volume-to-volume water-ice mixture and extract dichloromethane. The organic phase is dried over MgSO4, filtered and evaporated. The crude product is purified by crystallization from hexane to obtain 5.69 g of a white solid, 4 - [- 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-oxo-2-ethyl ~ bromobenzene (Yield = 63%) -F (~ C) = 197-1 H NMR 200 MHz (CDCl 3): 1.31 (s, 6H, 2 Me); 1.32 (s, 6H, 2 Me); 1.72 (s, 4H, 2 -CH2-); 4.22 (s, 2H, BnzH);
7.16 (d, 2H, ArH J 8.5 Hz); 7.44 (d, 2H, ArH J 8.5 Hz); 7.41 (d, 1H, ArH, ~ 8, SHz); 7.77 (dd, 1H, ArH ~ 1.8Hz J 8.5Hz);
8.02 (d, 1H, ArH 3 1.8Hz).
NMR13C 50MHz (CDC13): 31.6; 31.8; 34.4; 34.7;
34.8; 44.7; 120.8; 125.7; 127.0; 127.1; 13I, 3 - (2C); 131.6 (2C); 133.8; 133.9; 145.4; 15f, 0; 196.6. ~~
MS IC butane (m / z, ~ intensity): 387, 385 (MH, 100%, 97%).
d) Preparation of 4- ~ 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -1- (hydrQxy) -2-ethyllbxomobenzene from ~ ormule:

W 097J26237 PCTfi ~ R97 / W079 ~ 113 ~ Br To a solution of 4 - [- 1- (5,6,7,8-tetrahydro-5,5,8, ~ -telramethyl-2-naphthalenyl) -1-oxo-2-ethyl ~
bromobenzene (3.85 g, 10.0 mmol) in 30 ml of THF, add to - 70 ~ C a solution of phenyllithium 1.9 M in a toluene: ether mixture = 3: 1 (8.6 ml, 12.0 mmol). We continues stirring at -70 ~ C for 45 min then hydrolysis per 25 ml of a saturated NH4Cl solution. We go back to room temperature and extracted with ether (5 x 50 ml), dries on MgSO4, filters and evaporates. The gross product is purifies by flash chromatography on silica (eluent ether petroleum: ether = 100: 5). 2.48 g of one are obtained.
white solid, 4 - [- 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napht ~ lenyl) -1- (phenyl) -1- (hydroY.y) -2-ethyl] bromo-benzene (Yield = 53 ~).
F (~ C) = 130-132.
1 H NMR 200 MHz (CDCI 3): 1.20 (s, 12 H, 4 Me); 1.60 (s, 4H, 2 -CH2-) i 3.52 (s, 2H, BnzH); 6.22 (d, 2H, ArH J
8Hz); 7.05 (dd, 1H, ~ 2Hz J 8Hz); 7.15-7.45 (m, 10H, ArH).
e) Preparation of (E) and (Z) 4- ~ 1- (5.6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl ~ -1- (phenvl) -2-ethenyllbromobenzenes of the following respective formulas:

WO 97/26237 PCT ~ FR97 / 00079 Br (E) Br ~

(Z) To a solution of 4 - [- l- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -l- (phenyl) -1- (hydro ~ y) -2-ethyl] bromobenzene (2.48 g, 5.34 mmol) in 26 ml S of ethanol, a room temperature is added 3N HCl solution (8.5 ml, 25.5 mmol) The medium reaction is brought to reflux for 2 h. After returning to ambient, add 25 ml of water and extract with ether (5 x 50 ml), dry over MgSO4, filter and evaporate. The product crude is recrystallized from ethanol and after filtration and drying 0.60 g of a white solid on (E) 4- [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -l-(phenyl) -2-ethenyl] bromobenzene (Yield = 25 ~) The filtrate is evaporated to dryness, then the crude product obtained puri ~ ié by lS flash chromatography on silica (eluent ether of oil). 1.13 g of an oil are obtained, the (Z) 4- [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -l-(phenyl) -2-ethenyl] bromobenzene (Yield = 47%) (containing about 10% of isomer (E) determined by NMR H).

WO 9712623'7 PCT / FRg7 ~ 00079 ~ 115 Isomer (E):
F (~ C) = 147.
1 H NMR 200 MHz (CDCl3): 1.10 (s, 6H, 2 Me); 1.15 (s, 6H, 2 Me); 1.62 (s, 4H, 2 -CH2-); 6.80-6.90 (m, 3H, H
vinyl and ArH); 6.95-7.05 (m, 1H, ArH); 7.10-7.35 (m, 9H, ArH ~.
Isomer (Z):
F (~ C) = 114.
1 H NMR 200 MHz (CDCl3): 1.05 (s, 6H, 2 Me); 1.27 (s, 6H, 2 Me); 1.65 (s, 4H, 2 -CH2-); 6.80-6.90 (m, 3H, H
vinyl and ArH); 7.07-7.12 (m, 1H, ArH); 7.15-7.40 (m, 9H, ArH).

f) Pré ~ aratio ~ du (E ~ (5,6,7,8 ~ étrahydro-5,5.8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyll benzene (compound CB04854) of formula:
'~
~ <~
To a solution of (E) 9- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] bromobenzene (80 mg, 0.18 mmol) in 2.2 ml of THF, a solution of n-butyllithium 1.6 M is added to - 70 ~ C
in hexane (0.12 ml, 0.19 mmol). Shake at - 70 ~ C
for 30 min then let the reaction medium rise to - 10 ~ C and hydrolyzed with 3 ml of a 3N HCl solution.
Extracted with ethyl ether (5 x 20 ml), dried over MgSO4, filters and evaporates. The raw product is recrystallized in methanol and we obtain after ~ iltration and drying 50 mg of a white solid, (E) [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] benzene (CB0485 ~? (Yield = 75%).

W097 / 26237 PCTn ~ R97 / 00079 F (~ C) = 157.
1 H NMR 200 MHz (CDCl 3): 1.25 (s, 6H, 2 Me); 1, 30 (s, 6H, 2 Me ~; 1.65 (s, 4H, 2 --CH2 -); 6.80--7.10 (m, 6H, H
vinyl and ArH); 7.15--7.35 (m, 8H, ArH).
MS EI 70 ev (m / z,% intensity): 366 (M, 100 ~); ~
351 (52); 179 (25).
MSHR EI 70 ev: Mtr = 366, 2339 for C28H30 Mth =
366.2347 E: example 17: ~ separation of the acid (E) 4- ~ l-(5,6,7,8-tetrahydro-5 ~ 5 ~ 8 ~ 8-tetramethyl-2-naphthalenyl) -l-(phenyl) -2-ethenyllbenzoic acid (compound CB0158 ~) of formula:

~ ~ COQH
, "~, ~ = DD
'Xw a) Prep ~ ration of (E) 4- ~ l- (5 6 7, 8-tét ~ rahydro-5 5.8 8-tetramethyl-2-n ~ ht ~ lenyl) -1- (~ hényl) - -ethenyllhenzonitrile of formula:

~, _ ~ CN

To a solution of (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] bromobenzene (0.24 g, 0.53 mmol) in 1 ml of DMF
anhydrous, the cyanide of copper (55 mg, 0.61 mmol). The reaction medium is carried at reflux for 4 h. After returning to room temperature the reaction medium is diluted with ether (10 ml) and CA 02243295 l998-07-l3 WO 97 / 2623'7 PCTA ~ R97 / 00079 _ 117 filtered on celite. The organic phase is washed with a saturated aqueous solution of NaHCO3 (3 x 25 ml) then dry on MgSO4, filter and evaporate. The raw product is purified by flash chromatography on silica (eluent ether of petroleum: ether = 100: 2). 30 mg of a solid are obtained, (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] benzonitrile (Yield = 14 %) F (~ C) = 191-193.
1 H NMR 200 MHz (CDCI 3): 1.10 (s, 6H, 2 Me); 1.15 (s, 6H, 2 Me); 6.90 (s, 1H, vinyl H); 6.78-7.10 (m, 3H, ArH); 7.15-7.50 (m, 9H, ArH).
MS EI 70 ev (m / z,% intensity): 391 (M, 100%);
376 (90); 204 (40).
b) Preparation of the acid (E) 4- ~ 1- (5 6 7.8-tetrahydro-5 5 8 8-tetramethvl-2-naphthalenvl) -1- (phenyl) -2-ethenyllbenzoic (compound CB01585).
A suspension of (E) 4-L1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] benzonitrile (30 mg, 0.076 mmol) dissolved in potash (42 mg, 0.75 mmol) hydroethanolic (H2O 0.1 ml and EtOH 1 ml) is heated to reflux with stirring magnetic for 12 h. The ethanol is evaporated at the rotary evaporator ~, takes up in water (10 ml), acidifies with 3N HCl, extracted with ethyl ether (3 ~ 15ml), dry the ethereal phase on MgSO4, filters and evaporates. The product is washed with pentane, filtered and dried. We get 20 mg of a white solid, acid (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] benzoic (CB01585) (Yield = 64%).
F (~ C) = 240-241.
1 H NMR 200 MHz ICDC13): 1.20 (s, 6H, 2 Me); 1.25 (s, 6H, 2 Me) i 1.65 (s, 4H, 2 -CH2-); 4.40-5.15 (m, 1H, H
mobile); 6.80-7.40 (m, 11H); 7.60 (d, 2H, J 8, lHz).
MS EI 70ev (m / z,% intensity): 410 (M, 100%);
395 (6 ~, 9); 223 (17.5); 178 (10.2).

CA 02243295 l998-07-l3 WO 97/26237 PCTn ~ R97 / 00079 MSHR EI 70 ev: Mtr = 410.2238 for C ~ 9H30 ~ 2 Mth =
410.2246.
HPLC Column Waters HR Clg, 8 x 100 mm, 6 ~, Waters 486 Uv detector at 260 nm, flow rate 3 ml / min, eluent 5MeOH: H2O = 90: 10 + 0.1% TFA, acid (CB01585) tr =
5.0 min 97.0 ~.

~ xample 18: Preparation of acid (Z) 2- r 1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyllpyridinyl-5-carboxylic (compound CB3841 ~) of ~ formulates:
HOOC ~

a) Preparation of ~) and (Z) 2 ~ (5.5 7 8-tetrahydro-5 5,8,8-tetramethyl-2-naphthalenyl) -2- =
lS ~ methyl ropenyllpyridinyl-5-carboxvlates of formulas following resp: cives:

WO 9712623, 'PCTAFR97 / 00079 _, ~ _ COOMe J ~ ~ N

MeOOC

NOT
~ (Z) A bromide solution of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -methyl- triphenylphosphonium (1.80 g, 3.3 mmol), NaH (Aldrich, 3.3 mmol) from 0.12 g of a dispersion of 60% NaH in oil in 10 ml of anhydrous ~ MSO is stirred under argon for 30 min, then a solution of 2-acetylpyridine-5- is added methyl carboxylate (0.50 g, 2.79 mmol) in l ml of DMSO. The solution is stirred for ~ 70 h at room temperature and then poured over ice (50 g). Then extracted with ether (5 x 50 ml). The raw product is purified by flash chromatography on silica (eluent petroleum ether : ethyl ether ether = 100: 10). 0.64 g of a mixture of (E) and (Z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-5-methyl carboxylates (Yield = 63%) in solid form (ratio (E): (Z) about 47: 53 determined by H NMR
200MHz).
1 H NMR 200 MHz (C ~ C13): 0.95 (s, 6 x 0.53 H, 2 Me, isomer Z); 1.18 (s, 6 x 0.53H, 2 Me, Z isomer); l, 28 (s,

- 12 x 0.47H, 4 Me, isomer E); 1.55 (s, 4 x 0, q7H, 2 -CH2-, W 097/26237 PCTn ~ R97 / 00079 _ 120 isomer E) i 1.68 (s, 4 x 0.53H, 2 -CH2-, isomer Z); 2.25 (s, 3 x 0.47H, vinyl Me, E-isomer); 2.37 (s, 3 x 047H, Vinyl (Z isomer); 3.91 (s, 3 x 0.53H, -OMe, isomer Z); 3.93 (s, 3 x 0.47H, -OMe, isomer E); 6.60-6.85 (m, 2H); 7.00-7.40 (m, 2H, ArH); 7.60 (m, 1H, ArH); 8.05-8.45 (m, 1H, ArH); 9.15-9.25 (m, 1H).
b) Acid (Z) 2-rl- (5,6,7,8-tetrahydro-5,5 8,8-tetramethyl-2-naphthalenyl) -2-propenyllpyridinyl-5-because ~ oxylic (compound C338416) A suspension of (E) and (Z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -methyl pyridinyl-5-carboxylates and (0.64 g, 1.76 mmol) in solution in potash ~ 0.5 g, 9 mmol) hydromethanol (H2O 2.2 ml and MeOH 19 ml) is heated to reflux under magnetic stirring for 12 h. The methanol is evaporated at the rotary evaporator, take up in water (50 ml), acidify with 3N HCl, extract (3 x 50ml) with ether, dries the ethereal phase on MgSO4, filter and evaporate. The crude product is purified by Preparative HPLC on a Waters HR C1g column (25 x 100 mm) with MeOH as eluent: H2O = 85: 15 ~ 0.1% of TFA. We obtains 108 mg of a white solid, acid (Z) 2 - [(1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2- ~ =
propenyl] pyridinyl-5-carboxylic (CB38416) (Yield = 17 ~.
F (~ C) = 234-236.
1 H NMR 200 MHz (DMSO-d6): 0.91 (s, 6H, 2 Me); 1.13 (s, 6H, 2 Me); 1.52 (s, 4H, 2 -CH2-); 2.12 (s, 3H, Me vinyl); 3.40 (m, 1H); 6.67 (m, 1H, vinyl H); 6, 70 (m, 1H, ArH); 7.10 (d, 1H, ArH J 8H7); 7.24 (d, 2H, ArH J
8Hz); 8.10 (dd, 1H, ArH J 2Hz J 8Hz); 9.15 (m, 1H, ArH).
MS El 70 ev (m / z, ~ intensity): 349 (56%); 348 (100); 334 (39); 278 (11); 262 (19).
MSHR EI 70 ev: Mtr = 349.1968 for C23H27NO2 Mth = 349.2042.
HPLC Column Waters HR C1g, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent CA 02243295 l998-07-l3 WO 97/26237 PCT ~ P ~ 97 / W079 .

MeOH: H20 = 85: 15 + 0.19 ~ of TFA, acid (CB38416) tr =
2.8 min 98.5%.

~ xample 19: Preparation of the acid ~ E) 5 ~
(5, ~, 7.8 - tetrahydro-5,5,8,8-tetramethyl - 2 - naphthalenyl) -2--propenyllpyrldinvl-2-carboxylic (compound CBl2273) of formulates COOH

, ~~ N

a) Preparation of (F.) and (Z) 5 - r l-- (5, 6,7,8--Tet ~ hvdro-5,5,8,8-tetxamethyl-2-naphthalenyl) -2-propenyll pyri ~ linyl-2- (N, N-dilso ~ ropyl) carhoxamides of formulas respectively:
CONiPr2 ~ E) NOT

~ 1 ( ><~
- To a bromide solution of (5, 6,7,8-tetrahydro-lS 5,5,8,8 - tetramethyl-2-naphthalenyl) methyl-triphenylphosphonium (9.34 g, 17.2 mmol) in 25 ml of THF, a solution of tBuOK (2.13 g, 18.1) is added to - 70 ~ C

CA 0224329 ~ l998-07-l3 WO 97/26237 PCT ~ FR97tO0079 _ 122 mmol) in 18.1 ml of THF. We continue the agitation at - 70 ~ C for 1 h before adding N, N- at this temperature diisopropyl-5-acetyl-pyridine-2-carboxamide.
The reaction medium is brought to temperature ambient and stirring is continued for 90 h. We then hydrolyzes at 0 ~ C by. 3N HCl solution (30 ml). After returning to ambient temperature, it is extracted at ether, dry over MgSO4, filter and evaporate the solvents.
The crude product is purified by flash chromatography on silica (eluent: petroleum ether: ether = 100: 25). We 0.60 g of a solid is obtained, the (E) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2- (N, N-diisopropyl) carboxamide then 0.50 g of a white solid le (Z) 5- ~ 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-(N, N-diisopropyl) carboxamide and 0.78 g of the mixture of the two isomers (overall yield = 60%).
Isomer (E):
1 H NMR 200 MHz (CDCl 3): 1.05-1.25 (m, 6H, 2 Me);
1.30 (s, 12H, 9 Me); 1.40-1.60 (m, 6H, 2 Me); 1.70 (s, 4H, 2 -CH2-); 2.30 (s, 3H, Me); 3.50 (m, 1H, -CH-N-); 3.90 (m, 1H, -CH-N-); 6.80 (m, 1H, vinyl H); 7.10-7.18 (m, 1H, ArH), 7.25-7.35 (m, 2H, ArH); 7.45 (d, 1H, ArH J 8Hz); 7.62 (dd, 1H, ArH J 2Hz and J 8Hz); 8.70 (m, 1H, ArH).
Isomer (Z):
1 H NMR 200 MHz (CDCl 3): 0.97 (s, 6H, 2 Me); 1.05-1.25 (m, 12H, 4 Me); 1.40-1.70 (m, 10H, 2 -CH2- and 2 Me);
2.22 (s, 3H, Me); 3.97 (m, 1H, -CH-N-); 4.92 (m, 1H, -CH-N);
6.52 (s, 1H, vinyl H); 6.72 (dd, 1H, ArH J 2Hz J 8Hz);
6.85 (m, 1H, ArH); 7.05 (d, 1H, ArH J 8Hz); 7.30-7.90 (m, 1H, ArH); 7.57 (dd, 1H, ArH J 2Hz J 8Hz); 8.37 (m, 1H, ArH).
b) Preparation of (E) 5- ~ 1- (5,6,7,8-tetrahydro-5 5.8 8-tetramethyl-2-naphthalenyl) -2-propenyll-2-formylpyridine of formula:

CA 02243295 l998-07-l3 WO 97126Z3'1 PCT ~ FR97 / 00079 _ 123 ~ CHO

To a solution of (E) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8 tetram ~ thyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-(N, N-diisopropyl) carboxamide (0.51 g, 1.40 mmol) in 7 ml of THF, a hydride solution of -70 ~ C is added 1.5 M diisobutylaluminum in toluene (1 ml, 1.47 mmol) Stir at this temperature 30 min and hydrolyzed with an aqueous solution of 3N HCl (5 ml), rises to room temperature and extracted with dichloromethane (5 x 20 ml). The organic phase is dried on MgSO4, filtered and evaporated. The raw product is purified by flash chromatography on silica (eluent ether of petroleum: ether = 100: 20). 0.14 g of a solid is obtained white, (E) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -2-formylpyridine (Yield = 29%).
1 H NMR 200 MHz (CDCl 3): 1.27 (s, 12 H, 4 Me); 1.67 (s, 9H, 2 -CH2-); 2.30 (s, 3H, Me); 6.93 (s, 1H, H
vinyl); 7.10-7.20 -m (m, 1H, ArH); 7.28-7.37 (m, 2H, ArH);
7.93 (m, 2H, ArH); 8.90 (m, 1H; ArH); 10.07 (s, 1H, -CHO).
c) Preparation of ~ Z) 5- ~ 1- (5 6 7.8-tet ~ hydro-S 5 8 8-tetramethyl-2-naphthalenyl) -2-propenyll-2-formylpyridine of formula:
OHC

N ~
~ I
~ 3 ' CA 0224329 ~ 1998-07-13 W 097/26237 PCT ~ R97 / 00079 To a solution of the (z) 5- [1- (5, 6, 7, 8--tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl]
pyridinyl-2- (N, N-diisopropyl) carboxamide (0.26 g, 0.71 mmol) in 3.5 ml of THF, a solution is added at -70 ~ C
S of diisobutylaluminum hydride 1.5M in toluene (0.5 ml, 0.75 mmol). It is stirred at this temperature for 30 min and hydrolysis with an aqueous solution of 3N HCl (5 ml), rises to room temperature and extracted with dichloromethane (5 x 20 ml). The organic phase is dried on MgSO4, filtered and evaporated. The hrut product is purified by flash chromatography on silica (eluent ether of petroleum: ether = 100: 20). 0.15 g of a solid is obtained, la (Z) 5- [1 - (5, 6,7,8,8 - tetrahydro-5,5, 8, 8 - tetramethyl - 2--naphthalenyl) -2-propenyl] -2-formylpyridine (Yield = 63%).
1 H NMR 200 MHz (CDCl 3): 0.93 (s, 6H, 2 Me); 1.20 (s, 6H, 2 Me) 1.55 (s, 4H, 2 --CH2 -); 2.20 (s, 3H, Me);
6.62 (s, 1H, vinyl H); 6.67--6.78 (m, 211, ArH); 7.05 (d, 1H, ArH J 8Hz); 7.65-7.72 (m, 1H, ArH); 7.87 (d, 1H, ArH .T
8Hz); 8.55 (m, 1H, ArH); 9.98 (s, 1H, -CHO).
d) Preparation of (E) e ~; (Z) 5-r-1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyll methyl pyridinyl-2-carboxylates of respective formulas following W 097 / 2623'7 PCTn ~ R97 ~ 79 _ 12 ~

~ COOMe ., II

. '~ N
~ ~) MeOOC

NOT
~ 1 ~ z ~

To a solution of the mixture of (E) and (Z) 5- [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -2-formylpyridines (0.72 g, 2.17 mmol) in 60 ml of methanol, 0.185 ml of acetic acid is successively added, manganese oxide (3.98 g, 43.3 mmol) and cyanide sodi4m (0.53 g, 10.85 mmol) at room temperature. The middle The reaction mixture is stirred at this temperature for 15 h. We filter on paper, evaporate and take up in 20 ml of water, ether extract (5 x 50 ml), dry over MgSO4, filter and evaporates. The crude product is purified by chromatography flash on silica (eluent petroleum ether: ether = 100: 20 then 100: 25). Obtained after evaporation of ~ reactions 0.13 g of a solid, the (Z) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-carboxylate methyl (yield = 16 ~) then 0.11 g of a solid, the ~ E) 5- [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-methyl propenyl] pyridinyl-2-carboxylate (yield = 14% ~.
Isomer (E):
1 H NMR 200 MHz (CDCl3): 1.25 (s, 12H, 4 Me); 1.70 (s, 4H, 2 -CH2-) i 2.35 (s, 3H, Me) i 4.00 (s, 3H, -OMe);

CA 0224329 ~ 1998-07-13 WO 97/26237 PCT ~ R97 / 00079 6.90 (s, 1H, vinyl H); 7.12 (dd, 1H, ArH J 2Hz J 8Hz);
7.25-7.35 (m, 2H, ArH); 7.87 (dd, 1H, ArH J 2Hz J 8Hz);
8.10 (d, 1H, ArH J 8Hz); 8.85 (m, 1H, ArH).
Isomer ~ 3:
1 H NMR 200 MHz (CDCl 3): 0.90 (s, 6H, 2Me); 1.17 (s, 6H, 2 Me); 1.52 (s, 4H, 2 -CH2-); 2.40 (s, 3H, Me);
4.00 (s, 3H, -OMe ~; 6.50-6.85 (m, 3H, vinyl H and ArH);
6.95-7.15 (m, 1H, ArH); 7.20-7.75 (m, 2H, ArH); 8.02 (d, 1H, ArH J 8Hz); 8.47 (m, 1H, ArH).
e) Preparation of the acid (~) 5- r 1- ~ 5.6 7 8-tetrahydro-5.5 8 8-tetramethyl-2-naphthalenyl) -2-pro ~ enyll pyridinyl-2-carboxy ~ ique (CB12273) A suspension of (E) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-1 ~ methyl carboxylate, (80 mg, 0.22 mmol) in solution in potassium hydroxide (120 mg, 2.18 mmol) hydromethanolic (H2O
0.3 ml and Me ~ H 2.4 ml) is heated to reflux with stirring magnetic for 3 h 30 min. The methanol is evaporated at the rotary evaporator, take up in water (10 ml), acidify with 3N HCl, extract (3 x 20ml) with ether, dry the phase ethereal on MgSO4, filter and evaporate. The gross product is washed with pentane and then filtered, 70 mg of a solid are obtained white, acid (E) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-carboxylic ~ CB12273) (Yield = 91%).
F (~ C) = 192.
1 H NMR 200 MHz (CDCI 3): 1.28 (s, 12 H, 4 Me); 1.69 (s, 4H, 2 -CH2-); 2.34 (s, 3H, Me); 6.85-7.05 (m, 1H, H
vinyl); 7.10-7.20 (m, 1H, ArH); 7.30-7.40 (m, 2H, ArH);
8.0-8.10 (m, 1H, ArH); 8.15-8.30 (m, 1H, ArH); 8.75-8.95 (m, 1H, ArH).
MS EI 70 ev (m / z,% intensity): 349 (M, 100%);
334 (96); 316 (20); 190 (20).
MSHR EI 70 ev: Mtr = 349.2045 for C23H27NO2 Mth = 349.2042.
IR (cm): 3738; 2994i 1706; 1578; 1464.

WO g7 / 26237 ~ cr / FRs7m (~ 07s _ 127 .

~ xample 20: Preparation of acid (E) 2- r 1-(5 ~ 6 7 ~ 8-tetrahydro-5,5 ~ 8,8-tetramethyl-2-naphthalenyl) -2-prQpényl) lthienyl-4-carboxvliaue compound (CB80660) of formula :
COOH
s a) P ~ eparation of 4-bromo-2- (1'-hydroxyethyl) -thiophene.
In a balloon fitted with a thermometer, under argon atmosphere and magnetic agitation, we bring to -70 ~ C a solution of 4-bromo-2-thiophenecarboxaldehyde (Aldrich, 1.20 g, 6.28 mmol) in 15 ml of ethyl ether anhydrous. A solution is then added dropwise of MeLi 1.6 M in ether (4.12 ml, 6.59 mmol) between -70 ~ C and -60 ~ C ~ Stirring is continued for 90 min at lS -60 ~ C. ~ the reaction is followed by CCM (eluan ~ ether: ether petroleum = 20:80). Hydrolysed at ~ roid with 5 ml of a saturated NH4Cl solution, add 20 ml of distilled water and extracted with ether (3 x 40 ml) ~ Dried over MgSO4 é ~ héré phase, filter and evaporate to obtain 1.28 g of a slightly yellowish oil, 4-bromo-2- (1'-hydroxyethyl) thiophene (gross yield = 98.5%).
1 H NMR 200 MHz (CDCl 3): 1.53 (d, 3H, Me J 6 Hz);
2.35 (broad s, 1H mobile, -OH); 5.02 (q, 1H, -CHOH J
6.0Hz); 6.84 (d, 1H, ArH J 1.5 Hz); 7.09 (d, 1H, ArH J
1.5Hz).
b) Preparation of 4-bromo-2-acetyl-thiophene.
In a flask fitted with a magnetic stirrer and under an argon atmosphere, a solution of Crude 4-bromo-2- (1'-hydroxyethyl) thiophene (1.28 g, 6.18 mmol) and PCC (2.66 g, 13.26 mmol) in 20 ml of dichloromethane. Shake vigorously for 2 h at WO 97/26237 PCT ~ R97 / 00079 .

room temperature, the reaction medium becomes gradually black. We then filter on column of florisil (eluent ether), evaporates the solvent and purifies the crude product obtained by flash chromatography on silica (eluent pure petroleum ether). 1.10 g of a white solid, 4-bromo-2-acetyl-thiophene (Yield = 87%).
1 H NMR 200 MHz (CDCl3): 2.50 (s, 3H, Me); 7.50 ts, 1H, ArH); 7.54 (s, 1H, ArH).
c) Prepaxation of (E) and (Z) 2-rl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenvl) l-4-hromothiophenes with the following res ~ ective formulas:
Br (E) Br ~ (Z) In a 100 ml bicol, equipped with a thermometer, magnetic stirring and under an argon atmosphere, year a weighed (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-) bromide 2-naphthalenyl) methyl triphenylphosphonium (7.00 g, 12.56 mmol) dissolved in 20 ml of anhydrous THF. We add to -70 ~ C of tBuOK lM in THF and continue stirring at -70 ~ C for 1 h. We then add the 4-bromo-2-acetyl-thiophene (1.29 g, 6.28 mmol) in solution CA 02243295 l998-07-l3 WO 97/26237 PCT ~ FR97 / 00079 129 in 15 ml of anhydrous THF and then gently raise the reaction medium at room temperature and continues agitation for 72 h. We then pour the middle reaction in a water-ice solution and extracted with ether (5 x 50 ml). The organic phase is dried with MgSO4, filtered and evaporated to yield a crude product that we puri ~ ie by flash chromatography on silica (eluent pure petroleum ether). 1.97 g of a colorless oil composed of the mixture of isomers of ~ E) and (Z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] - 4-bromothiophenes (overall yield =
80 ~) (ratio (F): (Z) = 60: 40 determined by NMR H).
NMR H 200 MHz (CDC13): 1.15 (s, 6 x 0.40 H, 2 Me, Z isomer); 1.25 (s, 6 x 0.40 H, 2 Me, Z isomer); 1.30 ~ 5 (s, 12 x 0.60 H, 4 Me, isomer E); 1.62 (s, 4 x 0.40 H, 2 -CH2-, Z isomer); 1.70 (s, 4 x 0.60 H, 2 -CH2, E-isomer);
2.20 ~, 3 x 0.40 H, Me J 2.9 Hz, isomer Z); 2.27 (d, 3 x 0.60 H, Me ~ 2.9 Hz, isomer E); 6.51 (s wide, 1 x 0.40 H, Vinyl H, Z isomer); 6.75-7.35 (m, 5H, ArH E isomers and Z and 1 x 0.60 H, vinyl H isomer E).
d) Preparation of (E) 2- ~ 1- (5 6 7 8-tetrahydro-5 5 8 8-tetramethyl-2-naphthalenyl) -2- ~ ropenyl) lthienyl-4-carbcx ~ late methyl of the following formula:
COOMe In a 25 ml flask fitted with a stirrer magnetic, thermometer and argon on atmosphere introduced a solution of (E) and (Z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] -4-bromothiophenes Z and E (1.22 g, 3.13 mmol) in solution in 12.5 ml of anhydrous THF. We carry the reaction medium a -70 ~ C and add dropwise a solution of t-CA 0224329 ~ 1998-07-13 WO 97/26237 PCT ~ FR97 / 00079 1.7 M butyllithium in pentane (3.78 ml, 6.42 mmol). The reaction medium darkens and stirred for 20 min at -70 ~ C then add methyl chloroformate (1.5 eq., 4.70 mmol) and brings the reaction medium to room temperature for 30 min. We add to 0 ~ C 25 ml distilled water and extracted with ether (3 x 50 ml), dry the organic phase on MgSO4, filters and evaporates. We obtain a crude product which is purified by flash chromatography on silica (eluent petroleum ether then ether: ether of petroleum = 2: 98). 0.10 g of a white solid is obtained.
(E) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] methyl thienyl-4-carboxylate after recrystallization from hexane (Yield = 8%).
1 H NMR 200MH ~ (CDC13): 1.28 (s, 12H, Me ~; 1.68 1S (s, 4H, 6.7-CH2-); 2.29 (d, 3H, Me J 2, gHz); 3.87 (s, 3H, -OMe); 7.02-7.33 (m, 5H, vinyl ArH and H); 7.68 (d, 1H, ArH ~ 10Hz).
e) Preparation of ~ cide (E) 2- ~ 1- (5 6.7 8-tet ~ hydro-5 5.8 8-tetramethyl-2-naph ~ alenyl ~ 2-propenyl) l-thienyl-4-carboxylic (compound C ~ 80660).
In a 10 ml flask fitted with a condenser and under magnetic stirring, a previously introduced suspension of (E) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] thienyl-4-methyl carboxylate (88 mg, 0.24 mmol) in 3 ml of m ~ thanol and 1.5 ml of an aqueous solution of KOH 5N. We refluxed for 6 h, cools the medium reaction, acidifies with 3N HCl to pH = 1 and extracts with ether (3 x 30 ml). The ethereal phase is dried over MgSO4, filters and evaporates. The raw product is washed in a minimum of hexane and 40 mg of a white solid is obtained, the acid (E) 2- ~ 1- (5,6,7,8-tétrahydro-5,5,8,8-tétramethyl-2-naphthalenyl) -2-propenyl)] - thienyl-4-carboxylic (CB80660) (YId = 47%) -F (~ C) = 232-235.

WO 9712623'7 PCT ~ F ~ R5'7 / 00079 1 H NMR 200 MHz (CDCl 3): 1.28 ~ s, 12 H, 4 Me); l, 69 (s, 4H, -CH2-); 2.30 (s, 3H, Me); 7.00-7.35 (m, 5H, ArH and H
vinyl), 7.77 (d, 1H, ArH ~ 10Hz ~.
MS EI 70 eV (m / z,% intensity): 354 (M +, 100%); 339 (M + -CH3, 76); 297 (5); 155 (5).
MSHR EI 70 eV: Mtr 354.1661 for C22H26O2S Mth 364.1 ~ 54 -1 IR (NaCl tablets, cm): 1668 (C = O) -HPLC ODS Ultrasound Column, 5 ~, 250 x 4.6 mm, 10 UV detection, 260 nm, flow rate 1 ml / min eluting MeOH: H2O =
100: 0 + 0.1% TFA, acid (C ~ 80660) tr = 4.6 min 98.9%, impurity tr = 4.1 min 1.1 ~.

Examples 21 and 22: Preparation of the acid (Z) 2-15 rl- (5,6,7.8-tetrahydro-5 5 8,8-tetramethyl-2-napht ~ lenyl) -2-propenyl) lthienyl-5-carboxylic (compound CB30382) of formula:
- HOOC
S ~ ~
~ 1 Preparation of the acid (F.) ~ - r 1- (5.6 7 8-tetrahydro-5 5 8,8-tetramethyl-2-naphthalenyl) -2-propenyl) lthienyl-5-c ~ rboxylic (compound CB38973) of formula :
J. ¦. ~ COOH

a) (E) and (Z) 2-rl- (5,6 7,8-tetrahydro-5,5,8 8-tetramethyl-2-naphthalenyl) -2-pro ~ enyl) l-5-bromothiophenes of the following respective formulas ~

CA 0224329 ~ 1998-07-13 W 097/26237 PCT ~ FR97 / 00079 ~ r Br ~ ~
S ~
~ 1 L 1 ~
> ~
To a bromide solution of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) methyl-triphenylphosphonium (3.34 g, 6.15 mmol) in 9 ml of THF, If a solution of tert-butylate of 1M potassium in THF (6.50 ml, 6.50 mmol). We continue stirring at - 70 ~ C for 1 h before ~ adding the 2-acetyl-5-bromothiophene (0.63 g, 3.10 mmol). The middle reaction is brought to room temperature and stirred for 20 h. Then hydrolyzed at 0 ~ C with a solution of 3N HCl. After returning to room temperature, extract with ether, dry over MgSO4, filter and evaporate the solvents.
The crude product is purified by flash chromatography on silica (eluent petroleum ether). 0.46 g of (E) is obtained lS and (Z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl ~] -5-bromothiophenes (yield = 38%) (ratio (Z): (E) = 70:30 determined by H NMR).
1 H NMR 200 MHz (CDCl3): 1.25-1.40 (m, 12H, 4 Me);
1.65 (s, 0.3 x 4H, 2 -CH2- isomer E); 1.70 (s, 0.7 x 4H, 2 -CH2- isomer Z) i 2.18 (s, 0.3 x 3H, Me vinylic isomer E); 2.25 (s, 0.7 x 3H, vinylic isomer Z) i 6.95 (s, 0.30 x 1H, vinyl H isomer E); 6.67 (d, 0.7 x W, H

WO 97 / 2623'7 PCT ~ FR97 / 00079 vinyl: isomer ZJ 5Hz); 6.80-6.87 (m, 2H, ArH); 6.92-7.00 (m, 1H, ArH); 7.05-7.30 (m, 2H, ArH).
b) Preparation of acids (E) and (Z) 2-rl-(5.6 7.8-tetrahydro-5 5 8 8-tetramethyl-2-naphthalenyl) -2-pro ~ enyl) lthienyl-5-car ~ oxyliques respectively designated compo ~ sés CB38973 and CB303 ~ 2 and corresponding to the formulas:

COOH

HOOC ~
~ (Z) ~ W
To a solution of (E) and (Z) 2- [l- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] - 5-bromothiophenes (0.46 g, 1.18 mmol) in 14 ml of THF, add at -70 ~ C a solution of n-butyllithium -, 6 M in hexane (0.8 ml, 1.18 mmol) and stirred 30 min. We do barbct a stream of carbon dioxide through the medium reaction and stirred 30 min at -70 ~ C. We let go back to -10 ~ C and hydrolysis with a 3N HCl solution (15 ml). We extract with ether, dry over MgSOg, filter and evaporate. The crude product is purified by preparative HPLC on a column Waters HR C18 (25 x 100 mm) with MeOH as eluent: H2O = 90 : 10 + 0.1% TFA. 101.2 mg of a yellowish solid are obtained, (E) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- acid naphthalenyl) -2-propenyl)] thienyl-5-carboxylic (CB38973) (Rdt - 25%) and 62.9 mg of a yellowish solid, acid (Z) 2- [1-CA 02243295 l998-07-l3 WO 97/26237 PCT ~ R97 / 00079 (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] thienyl-5-carboxylic (CB30382) (Yield = 16 ~).
Acid (Z) 2- [1 ~~ 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] thienyl-5-carboxyllque (CB30382):
F (~ C ~ = 165-167.
1 H NMR 200 MHz (CDCl3): 1.09 (s, 6H, 2 Me); 1.23 (s, 6H, 2 Me); 1.62 (s, 4H, 2 -CH2-); 2.22 (s, 3H, Me);
6.57 (s, 1H, vinyl H); 6.87 (m, 2H, ArH); 7.06 ~ m, 1H, ArH); 7.18 (m, 1H, ArH); 7.64 (d, 1H, ArH J 1.9Hz).
MS EI 70ev (m / z, ~ intensity): 354 (100%); 339 (92).
MSHR EI 70 ev: Mtr = 354.1669 for C22H26O.2S Mth = 354.1654.
HPLC Column Waters HR C1g, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 2 ml / min, eluent MeOH: H2O = 90: 10 + 0.1% TFA, acid (CB30382) tr =
4.4 min 97.5 ~; impurity tr = 6.0 min l, 8%.
Acid (E) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] thienyl-5-carboxylic (CB38973):
F (~ C) = 239-1 H NMR 200 MHz (CDCl3): 1.28 (s, 12H, 4 Me); 1.66 (s, 4H, 2 -CH2-); 2.30 (s, 3H, Me); 7.15 (m, 3H, H
vinyl and 2 ArH); 7.28 (m, 2H, ArH); 7.77 (d, 1H, ArH J
2Hz).
MS EI 70 ev (m / z,% intensity): 354 (100 ~); 339 (95).

MSHR EI 70 ev: t ~ tr = 354.1667 for C22H26 ~ 2S Mth = 354.1654.
HPLC: Waters HR Clg column, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluting MeOH: H2O = 90: 0 + 0.1 ~ of TFA, aclde (CB38973) tr = 4.1 min 98.1%; impurerQ tr = 3.1 min 1.5 ~.

Examples 23:

WO 9712623, 'PCT ~ FR97 / 00079 -~ acid separation (Z) 5 ~ (5 6 7.8-tetrahydro-5,5,8 8-tetramethyl-2-naphthalenyl) -2-propenyl) l-isoxazole-3-carboxylic (CB73069) and acid (E) 5-rl-(5 6 7 8-tetrahydro-5 5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl) lisoxazole-3-carboxylic (CB57201) a) (E) and (Z ~ 5- ~ 1- (5,6,7 8-Tétrahydro-5 5 8 8-tetramethyl-2-naphthalenyl) -2-propenyl) lisoxazole-3-~ arbo ~ ethyl ylates To a bromide solution of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -6-methyltriphenyl-phosphonium 9 (4.75 g, 8.74 mmol) in 10 ml of THF
anhydrous, a solution of t-3uOK 1 ~ is added to -70 ~ C
THl- (6.50 ml, 6.50 mmol). We continue the agitation at -70 ~ C for 1 h before adding a solution of 5-acety: ethyl lisoxazole-3-carboxylate (0.80 g, 4.37 mmol) in 5 ml of anhydrous THF. The reaction medium is brought to room temperature and stirred for 16 h. We pour then the reaction medium on a water-ice mixture (150 ml) then extracted with ether (3 x 70 ml), dried over MgSOq, filters and evaporates the solvents. The raw product is purified by flash chromatography on silica (eluent ether: ether petroleum = 2: 98 then 5: 95). 0.37 g of a yellowish oil, the (Z) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] isoxazole-3-ethyl carboxylate (yield = 23%) then 0.65 g of a solid yellowish, the (E) 5- r 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl) Jisoxazole-3-ethyl carboxylate (Yield = 40.5 ~).
Isomer (Z):

CA 02243295 l998-07-l3 EK ~ OC
~ i RMN1H 200MHz (CDCl3): 1.16 and 1.25 (2s, 12H, 5.5,8.8-Me) i 1.31 (t, 3H, Me ~ 7, 1Hz); 1.64 (s, 4Hj 6.7-CH2-); 2.23 (d, 3H, vinyl Me J 1.5 Hz); 4.37 (q, 2H, -OCH2- J
7, 1Hz); 6.29 (s, 1H, H isoxazole); 6.74 (broad s, 1H, H
vinyl) i 6.91 (dd, 1H, ArH ~ 1.8Hz J 8, 1Hz); 7.11 (d, 1H, ArH J 1.8Hz) i 7.24 (s, 1H, ArH).
MS EI 70 eV (m / z,% intensity): 367 (M +, 48%);
352 (M + -CH ~, 100 ~; 253 (17); 74 (12); 59 (21); 57 (15); 55 0 (15).
Isomer (F.) Cost ,. I "~

(~ C) = 89.
1 H NMR 200MHz (CDC13): 1.29 and 1.31 (2s, 12H, 5,5,8,8-Me); 1.42 (t, 3H, Me ~ 7, 1Hz); 1.68 (s, 4H, 6.7-CH2-); 2.26 (d, 3H, vinyl Me J 1.4 Hz); 4.44 (q, 2H, -OCH2-7, 1Hz); 6.64 (s, 1H, H isoxazole); 7.19 (dd, 1H, ArH J
1.7Hz J 8.2Hz); 7.27-7.40 ~ m, 3H, 2 ArH and vinyl H).
MS EI 70 eV (m / z, ~ intensity): 367 (M +, 62%);
352 (M + -CH ;, 100); 253 (18).
b) Acid (z) 5- r1- (5 6.7 8-tetrahydro-5 5.8.8-tet ~ methyl-2-n ~ ht ~ lenyl) -2-propenyl ~ lisoxazole-3-c ~ rhoxylic (CR73069) In a 25 ml flask fitted with a rigorous re ~ and with magnetic stirring, (Z) 5- [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-WO 97 / 2623'1 PCTAFR97 / 00079 -propér.yl)] ethyl isoxazole-3-carboxylate (0.35 g, 0.95 mmol) suspended in 6.6 ml of ethanol and 1.1 ml of water distilled. Potash is added (0.53 g, 9.5 mmol) then brings the reaction medium to reflux for 8 h.
After the reaction medium has cooled, it is acidified with 3N HCl ~ until pH = 1 and extracted with ether (3 x 50 ml).
The ethereal phase is dried over MgSOq, filtered and evaporated. The crude product is purified by preparative HPLC on a Waters HR Cl8 column (25 x 100 mm) with MeOH as eluent : H2O = 85: 15 + 0.1% TFA. 0.31 g of a solid is obtained white, acid (Z) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] isoxazole-3-carboxylic (CB73069) (Yield = 96%).
HOOC

F (~ C) = 114.
RMN1H 200MHz (CDCl3): 1.16 and 1.25 (2s, 12H, 5,5,8,8-Me); 1.65 (s, 4H, 6.7-CH2); 2.24 (s, 3H, Me vinyl); 6.33 (s, 1H, H isoxazole), 6.77 (s, 1H, H
vinyl); 6.92 (d, 1H, ArH ~ 1.8Hz) 7.12 (s, 1H, ArH);
7.24 (d, 1H, ArH ~ 8.0Hz), 7.50 (broad s, 1H, -COOH).
MS IC 70 isobutane (m / z, ~ intensity): 340 (M ~ + l, 100%); 296 (57).
MSHR (FAB + NOBA): MH 340.1916 for C2LH25NO3 MH r ~ 3 ~ 0.1913 IR (KBr, cm): 1708 (mc ~
HPLC: Waters HR Ci8 column, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 85: 15 + 0.1 ~ of TFA, acid CB73069 tr = 3.37 min 97.6 ~.

WO 97/26237 PCT ~ R97 / 00079 c) Acid (E) 5-rl- (5 6.7 8-tetrahydro-5 5.8.8-tetram ~ thyl-2-naphthalenyl) -2-propenyl) lisoxazole-3-~
carhoxylic (CB57 ~ 01).
In a 50 ml flask fitted with a refractory ~ erant5 with magnetic stirring, the (E) 5- [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-ethyl propenyl)] isoxazole-3-carboxylate (0.70 g, 1.90 mmol) suspended in 13.2 ml of ethanol and 2.2 ml of water distilled. Potash is added (1.06 g, 19.00 mmol) lQ then brings the reaction medium to reflux for 1 h 15.
After cooling the reaction medium, acidify with 3N HCl until pH = 1 and extracted with ether (3 x 50 ml).
The ethereal phase is dried over MgSO4, filtered and evaporated. The crude product is taken up in a minimum of ethyl ether and hexane is added until precipitation occurs. After filtration and drying, 0.36 g of a white solid is obtained, acid (E) 5- ~ 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] isoxazole-3-carboxylic ~ CB57201) ~ Yield = 96%).
COOH

F (~ C) = 205.
RMN1H 200MHz (CDC13): 1.29 and 1.30 (2s, 12H, 5,5,8,8-Me); 1.69 (s, 4H, 6.7-CH2); 2.28 (d, 3H, Me vinyl J 1, 1 Hz); 6.71 (s, 1H, H isoxazole), 7.19 (dd, 1H, ArH J 0.8Hz J 4.0Hz); 7.25-7.45 (m, 3H, ArH and H
vinyl).
MS FAB + NOBA (m / z, ~ intensity): 340 (MH +, 100 ~); 324 (31); 154 (49); 136 (40).
MSHR (FAB + NOBA): MH tr 340.1917 for C ~ 1H25NO3 MH: 340.1913 HPLC: Waters HR C18 column, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, ~ glow WO 97 / 2623'r PCTn ~ R97 / 00079 MeOH: H2O = 85: 15 ~ 0.1 ~ TFA, CB57201 tr acid = 5.21 min 98.8 ~.
.

~ xample 24: ' S Acid preparation (Z) 5- r 1- (5.6 7.8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl) lisoxazole-3-carboxylic acid (CB54647) and acid (F.) 5- r 1- (5 6 7,8-tetrahydro-3,5 5 8 8-pentamethyl-2-naphthalenyl) -2-pro ~ enyl) 1isoxazole-3-carboxylic (CB82718) a) (E) and (Z) 5-rl- (5,6,7 8-Tétrahydro-3 5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl) lisoxazole-3-ethyl carboxylates.
To a bromide solution of (5, 6,7,8,8-tetrahydro-3.5.5 ~ 8.8-tetramethyl-2-naphthalenyl) -6-methyltriphenylphosphonium (4.86 g, 8.73 mmol) in 10 ml of TH] - anhydrous, a solution of t-BuOK lM is added at -70 ~ C
in THF (8.73 ml, 8.73 mmol). We continue the agitation at -70 ~ C for 1 h before adding a solution of 5-acety ~ ethyl isoxazole-3-carboxylate (0.80 g, 4.37 mmol) in 5 ml of anhydrous THF. The reaction medium is brought to room temperature and stirred for 3 h 30 min.
then the reaction medium on a water-ice mixture (150 ml) and 1N HCl (50 ml), then extracted with ether (2.: 75 ml) and with dichloromethane (2 x 75 ml), combines the phases organic which is dried over MgSO ~, filtered and evaporated. The crude product is purified by flash chromatography on silica (eluent ether: petroleum ether = 2: 98 to 10 : 90). 1.80 g of a colorless oil are obtained, the mixture of (E) and (Z) 5- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl) ~ isoxazole-3-ethyl carboxylates (Yield = 54%) in determined proportion by NMR; H 2 CO 0 MHz E: Z = 66:33.

CA 0224329 ~ 1998-07-13 W 097/26237 PCT ~ FR97 / 00079 Cost ~ '~
1 H NMR 200 MHz (CDC13): 1.12 (s, 0.33 x 6H, 2 Me isomer Z); 1.26 (m, 0.66 x 12H and 0.33 x 6H, 4 Me isomer E and 2 Me isomer Z); 1.32 (t, 0.33 x 3H, Me isomer ZJ
7, 1Hz); 1.42 (t, 0.66 x 3H, Me isomer ZJ 7, 1Hz); 1.63 (s, 0.33 x 4H, 6.7-CH2-Z isomer); 1.67 (s, 0.66 x 4H, 6.7-CH2-isomer E); 2.15 (d, 0.66 x 3H, E vinyl isomer Me 1.4Hz); 2.16 (s, 0.33 x 3H, aromatic Me isomer Z); 2.25 (s, 0.66; ~ 3H, aromatic Me isomer E); 2.29 (d, 0.33 x 3H, Me vinyl isomer Z ~ 1.4 Hz); 4.33 (~, 0.33 x 2H ~
-OCH2- Z isomer ~ 7.1 Hz); 4.45 (q, 0.66 x 2H, -OCH2-EJ 7 isomer, 1Hz); 5.95 (s, 0.33 x 1H, H isoxazole lsomer Z); 6.64 (s, 0.66 x 1H, H isoxazole isomer E); 6.78 (s, 0.33 1H, vinyl H isomer Z); 7.01 (s, 0.33 x 1H, ArH
isomer Z); 7.10-7.20 (m, 0.33 x 2H and 0.66 x 2H, ArH
Z isomer and ArH E isomer); 7.42 (s, 0.66 x 1H, H
vinyl isomer E).
b) Acids (Z) e ~ (~.) 5- ~ 1- (5.6 7,8-tetrahydro-3.5 5.8.8-pentamethyl-2-naphthalenyl) -2-pro ~ enyl) l isox ~ zole-3-c ~ rboxyliques CB54647 and CB82178.
In a 50 ml flask fitted with a condenser and with magnetic stirring, a mixture of (E) was introduced and (Z) 5 - [- 1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl) ~ ethyl isoxazole-3-carboxylates (1.80 g, 4.72 mmol) suspended in 26.0 ml of ethanol and 4.5 ml of distilled water. We add potash (2.12 g, 38.0 mmol) then reflux the reaction medium for 1 h 15. After cooling of the medium reaction, acidified with 3N HCl until pH = 1 and ether extract (3 x 70 ml). The phase ~ dried is dried on MgSO9, filter and evaporate to obtain 0.92 g of a mixture of acid (E) and (Z) (gross yield = 55%). Part of the CA 02243295 l998-07-l3 WO 97J2623'7 PCTtF ~ 97/00079 -crude product is puri ~ ed by preparative HPLC on a Waters HR Cl8 column (25 x 100 mm) with MeOH as eluent : H2O = 87: 13 + 0.1% TFA. 0.12 g of a solid is obtained white, acid 5 - [(Z) -1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl)] isoxazole-3-carboxylic acid (CB54647) and 0.23 g of a white solid, the acid (E) 5- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl)] isoxazole-3-carboxylic (CB8 ~ 178).
Acid (Z) 5 - [- 1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl)] isoxazole-3-carboxylic (CB54647):
HOOC ~

F (~ C) = 162-163.
lS RMN1H 200MHz (CDCl3): 1.11 and 1.26 (2s, 12H, 5,5,8,8-Me); 1.63 (s, 4H, 6.7-CH2); 2.17 (s, 3H, Me aromatic); 2.29 (s, 3H, vinyl Me); 5.99 (s, 1H, H
isoxazole), 6.80 (s, 1H, vinyl H); 6.99 ~ s, li, ArH);
7.12 (s, 1H, ArH).
MS FAB + NOBA (m / z, ~ intensity): 354 (MH +, 100 ~ li 338 ~ 35) i 154 (34); 136 (29).
MSHR (FAB + NOBA): MH, ~ 354.2072 for C2, H2, NO3 MH, ~ 354.2069 HPLC: Waters HR C18 column, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 87: 13 + 0.1% TFA, acid CB54647 tr = 3.28 min 99.1- ~; isomeric impurity (E) (CB82178) tr = 4.45 min 0.9 ~.
Acid (E) 5- [l- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl)] isoxazole-3-q carboxylic (CB82178):

W 097/26237 PCT ~ FR97 / 00079 C ~ O ~
> ~, ~ ,, ~, 1 F ~~ C) = 204 (dec.).
RMN1H 200MHz ~ CDCl3): 1.27 and 1.28 (2s, 12H, 5,5,8,8-Me); 1.68 (s, 4H, 6.7-CH2) i 2.16 (d, 3H, Me S vinyl J 1.2 Hz); 2.26 (d, 3H, aromatic Me); 5.63 (s broad, 1H, -COOH); 6.70 (s, 1H, H oxazole), 7.14 (s, 1H, ArH); 7.18 (s, 1H, ArH); 7.45 (d, 1H, vinyl H ~ 1.2Hz).
MS FAB + NOBA (m / z, ~ intensity): 3S4 (MH ~, 100%); 338 (36); 154 (25); 136 (19); 69 (12).
MSHR (FAB + ~ OBA): MH r_ 354.2069 for C22H27NO, MH th 354.2069 HPLC: Waters HR Cl8 column, 8 x 100 mm, 6 ~, Waters 486 UV detector at 26 ~ nm, flow rate 3 ml / min, eluent MeOH: H2O = 85: 15 ~ 0.1 ~ TFA, CB82178 tr acid =
4.53 min 99.6%, isomer impurity (Z) (CB54647) tr = 3.28 min 0.2 ~.
Example 25: Pre ~ aration of acid (E) 4-11-(5,6,7 8-tetrahydro-5 5 8 8-tetramethyl-2-naphthalenyl) -3-ethoxy-2-propenyllben ~ oic (CBl7231) a) (F.) 4- r 1- (5.6 7.8-tet ~ hydro-5 5 r 8.8-tetramethyl-2-naphthalenyl) -3-bromo-2-propenyllbenzoni ~ ri] e.
A solution of (E) 4- [1- (5,6,7,8-tetra ~ ydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] benzonitrile (0.27 g, 0.76 mmol), N-bromosuccinimide (0.16 g, 0.90 mmol), benzoyl peroxide (6 mg) in 3 ml CCl4 est brought to reflux for 2 h under an argon atmosphere and irradiation with a 500-W tungsten lamp. After cooling, the reaction medium is concentrated, taken up in ether and incorporated on silica. We purify by flash chromatography on silica (eluent ether: ether petroleum = 4: 96) to obtain a product after é ~ aporatiDn WO 97126237 P ~, I f ~ 7/00079 -crude which is recrystallized from hexane. We get 0.1Z
g of a white solid, the (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -3-bromo-2-propenyl] benzonitrile (Yield = 36.5 ~).
~ CN

F (~ C) = 151.RMNlH 200MHz (CDCl3): 1.29 and 1.32 (s, L2Hr 5,5,8,8-CH3); 1.70 (s, 4H, 6.7-CH2-); 4.54 (s, 2H, BnzH); 7.02 (s, 1H, H
vinyl); 7.2 ~ (dd, 1H, ArH ~ 2Hz J 8Hz); 7.37 (d, 1H, ArH J
lQ 8H ~); 7.54 (d, 1H, ArH ~ 2Hz); 7.67 (s, 4H, ArH).

b) Acid (E) 4- rl- (5 6,7,8-tetrahydro-5 5, ~, 8-tetramethyl-2-naphthalenyl) -3-ethoxy-2-propenvllbenzo ~ that (CB1,231).
IS A suspension of (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -3-bromo-2-propen ~ l] -benzonitrile (0.12 g, 0.28 mmol) in solution hydroethanolic (H2O 0.55 ml and EtOH 3.3 ml) is a, out of potash (0.50 g, 8.42 mmol). We heat at reflux ~ under magnetic stirring for 20 h. After cooling, acidified with 10 ml of a 1N HCl solution, ether (3 x 50 ml), dried with MgSO4, ~ ilter and evaporated. The crude product is purified by preparative HPLC on a Waters HR column C1g (25 x 100 mm) with MeOH as eluent : H2O = 85: 15 + 0.1% TFA. 0.03 g of a solid is obtained white, acid (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -3-ethoxy-2-propenyl ~ benzoic (CB17231) (Yield = 27%).
~ COOH

W 097/26237 PCT ~ R97 / 00079 -F (~ C) = 135.
1 H NMR 200 MHz (CDCI 3): 1.27 (t, 3H, Me ~ 7 Hz);
1.29 and 1.31 (s, 12H, 5,5,8,8-C ~ 3); 1.70 (s, 4H, 6.7-C ~ 2-);
3.59 (q, 2H, -OCH2- J 7Hz); 7.15 (s, 1H, vinyl H); 7.15-7.45 (m, 3H, ArH) i 7.89 (dm, 2H, ArH meta at -COOH J 8Hz);
8.09 (dm, 2H, ArH ortho at -COOH J 8Hz).
MS EI 70 eV (m / z, ~ intensity): 392 (M, 95 ~);
377 (66), 323 (14); 281 (37) i 215 (22); 149 (100); 91 (21);
71 (16); 69 (44) i 57 (47); 55 (46).
MSHR EI 70 eV: M = 398.2359 for C26H ~ 2O3 M ~ h =
392.2351.
HPLC: Waters HR Ci8 column, 8 x 100 mm, 6 ~, Waters 486 UV detector at 26 ~ nm, flow rate 3 ml / min, eluent MeOH: H2O = 85: 15 + 0.1% TFA, acid (CB17231) tr -7.12 min 98.3%; impurity tr = 4.73 min 1.40 ~.

~ xample 26: Pre ~ aration of (E) N-Carbethoxy-4-rl- (5,6,7 8-tetrahydro-5.5 8,8-tetramethyl-2-naphthalenyl ~ -2-propenyllaniline (CB21282) To an acid suspension (E) 9- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] benzoic (CB24159) (0.56 g, 1.61 mmol) in 5 ml toluene, successively add to the syringe diphenylphosphoryl azide (0.37 ml, 1.70 mmol) and triethylamine (0.24 ml, 1.69 mmol). We bring to 80 ~ C under argon atmosphere and magnetic stirring for 1 h.
After cooling, 0.95 ml of ethanol are added and then door at 80 ~ C for 3 h. We evaporate to dryness after cooling, resumed with ether and incorporated on silica.
The crude mixture is purified by flash chromatography on silica (eluent ether: petroleum ether = 3: 97 to 5 : 95). After evaporation, 0.50 g of a solid is obtained white, (E) N-carbethoxy-4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl ~ aniline (CB21282) (Yield = 79.5 ~).

W 097/26237 PCTnFR97 ~ aa79 ~ NHCOOEt F (~ C) = 124-5.
1 H NMR 200MHz (CDCl3): 1.31 and 1.32 (2s, 12H, 5,5,8,8-CH3); 1.30 ~ t, 3H, Me J 7.1 Hz); 1.71 (s, 4H, 6.7-CH2-); 2.28 (d, 3H, vinyl Me ~ 1.2Hz); 4.24 (q, 2H, -OCH2- J 7, 1Hz); 6.76 (br s, 1H, -NH-); 6.79 (s, 1H, H
vinyl); 7.15 (dd, 1H, ArH J 1.8Hz J 8.5Hz); 7.25-7.35 ~ m, 2H, ArH); 7.38 (d, 2H meta at -NH- J 8.7 Hz); 7.48 (d, 2H ortho at -NH- J 8.7 Hz).
MS EI 70 eV (m / z, 50 intensity): 391 (M +, 100%);
376 (~ g); 330 (17); 69 (25); 57 (17).
MSHR EI 70 eV: M ~ r = 391.2502 for C26H33NO2 Mth =
391.2512 - ~ PLC: Waters HR C column; s ~ 8: ~ 100 mm, 6 ~, detector ~ eur ~ V Waters 486 at 260 nm, flow 3 ml / min, eluent MeOH: H2O = 90: 10 + 0.1% TFA, N-carbethoxyaniline (CB21282 ~ tr = 4.04 min purity 97.6 ~; impurity-tr = 3.20 min 2.1%.

Example 2? : Preparation of (Z) N- (Carbethoxv) -4-- rl- (5,6,7,8-tetrahydro-5,5.8,8-tee ~ xamethyl-2-naphthalenyl) -2-pro ~ enyllaniline (CB96682) To a suspension of acid (Z) 4- [1- (5,5,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -benzcique (CB28628) (0.44 g, 1.26 mmol) in 4 ml of toluene, we successively add to the syringe diphenylphosphoryl azide (0.29 ml, 1.34 mmol) and triethylamine (0.19 ml, 1.33 mmol). We bring to 80 ~ C under argon atmosphere and magnetic stirring for 1 h.
After cooling, 1.0 ml of ethanol is added and then door at 80 ~ C for 3 h. We evaporate to dryness after cooling, resumed with ether and incorporated on silica.

WO 97/26237 PCT ~ FR97 / 00079 The crude mixture is purified by flash chromatography on silica (eluent ether: petroleum ether = 3: 97 to 5 : 95). 0.40 g of an oil is obtained after evaporation colorless, (Z) N- (carbethoxy) -4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] aniline (CB96682) (YId = 81%).
EtOOC-HN

F (C) = 47.
RMNlH 200MHz (CDCl3): 1.00 and 1.19 (2s, 12H, 5,5,8,8-CH3); 1.30 (t, 3H, Me J 7, 1Hz); 1.5 '(s, 4H, 6.7-CH2-); 2.14 (d, 3H, vinyl Me J 1.3 Hz); 4.21 (q, 2H, -OCH2- J 7, OHz); 6.37 (d, 1H, vinyl H J 1.3 Hz); 6.56 (s broad, 1H, -NH-); 6.74 (dd, 1H, ArH J 1.9Hz J 8.2Hz); 6.86 (d, 1H, ArH J 1.9 Hz); 7.04 (d, 1H, ArH J 8.2 Hz); 7.14 (dm, 2H, ArH meta at -NH- J 8.6 Hz); 7.48 ~ dm, 2H ortho to -NH- J
8.6Hz).
MS EI 70 eV (m / z, ~ intensity): 391 (M, 100 ~);
376 (49); 330 (14); 215 (31); 57 (14).
MSHR EI 70 eV: Mtr = 391.2512 for C26Hl-.NO ~ Mth =
391.2512 HPLC: Waters HR column C 8r 8: c 100 mm, 611, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 90: 10 + 0.1 ~ TFA, N-carbethoxyanlline (CB96682) tr = 3.17 min purity 98.8 ~; impurity tr = 1.45 min 0.6%.

Example 28: Pre ~ aratlon du (E) 1- ~ 4- ~ l- (5 6.7 8-Tetrahydro-5 5.8 8-tetramethvl-2-naphthalenyl) -2-pro ~ enyllphenyll-5-trifluorométhvl-1H-tetra ~ ole (CB59741) WO 97/26237 PCT ~ FR97 / 00079 a) (F.) 4- ~ 1- (5,6,7,8-'rétrahvdro-5 5 8 8-tetramethyL-2-naphthalenyl) -2-propenyllaniline.
A suspension of (E) ~ - (carbethoxy) -4-tl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-_ 5 propenyl] aniline (CB21282) (0.50 g, 1.28 mmol) in 10N sodium hydroxide (3.84 ml, 38.4 mmol) and 1.5 ml of ethanol is brought to 80 ~ C for 3 h under an argon atmosphere and magnetic agitation. After cooling, it is extracted with dichloromethane (4 x 25 ml), dry over MgSO4, filter and evaporates to obtain 0.31 g of a yellowish crude oil, the (E) 4-- [1- (5,6,7,8 - tetrahydro-5,5,8,8 - tetramethyl-2-naphthalenyl) -2-propenyl] aniline (Yield = 76 ~).

1 H NMR 200MH2 (CDC13): 1.37 and 1.38 (2s, 12H, lS 5,5,8,8-CH3); 1.77 (s, 4H, 6.7-CH2-) i 2.33 (d, 3H, Me vinyl J 1.2 Hz); 3.70 (br s, 2H, -NH2-); 6.72 (dm, 2H, ArH ~ r 8.6 Hz); 6.81 (d, 1H, vinyl H J 1.3 Hz); 7.21 (dd, 1H, ArH J 1.7Hz ~ 8.2Hz); 7.30-7.50 (m, 4H, ArH).
b) (E) N- (Trifluoroaceous ~ yl) -4- ~ 1- (5 6 7 8-2Q tetrahydro-5 5 8 8-tetramethyl-2-naphthalenyl) -2 propenyllaniline.
Mix for 30 min at room temperature, under an argon atmosphere, a solution of (E) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl ~ -aniline (0.31 g, 0.97 mmol) and 2-(tri ~ luoroacetoxy) pyridine (0.15 ml, 1.07 mmol) in 3 ml anhydrous ether. The ethereal phase is then washed with water distilled, dried over MgSO4, filtered and evaporated. We obtain 0.40 g of a yellowish solid, (E) N- (trifluoroacetyl) -4-[1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] aniline (crude yield 99%).

H
~ N ~ CF3 F (~ C) = 124.
1 H NMR 200 MHz (CDCl3): 1.28 and 1.29 (2s, 12H, 5, 5, 8, 8-CH3); 1.69 (s, 4H, 6.7-CH2-); 2.27 (d, 3H, Mevinylic ~ 1, OHz); 6.80 (s, 1H, vinyl H); 7.13 (dd, 1H, ArH J 1.8Hz J 8.0Hz); 7.27 (s, 1H, ArH); 7.30 ~ d, 1H, ArH J 8.0 Hz); 7.54 (s, 4H, ArH); 7.88 (broad s, 1H, --NH--).
RMN19F 50MHz (CDCl3): -76.23 (s, 0.77x3F, CF3 trans amide); -76.62 (s, 0.23x3F, CF3 cis amide).
c) Chloride of (F.) N- r4- rl- ~ 5 6,7,8-tétrahvdro-5,5,8,8-tét r ~ methyl-2-naphthalenyl) -2-propényllphényll-2 2 2-trifluoro ~ ketimidoyl A solution of (E) N-- (trifluoroacetyl) -4- [l-(5, 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] anlline (0.40 g, 0.96 mmol), of triphenylphosphine (0.60 g, 2.30 mmol) in 3.5 ml of carbon tetrachloride anhydrous is brought to reflux for 6 h under atmosphere of argon and magnetic agitation. After cooling, we evaporates the solvent, takes up in dichloromethane and incorporates on silica. The crude product is purified by chromatography flash on silica (eluent ether: petroleum ether = 4:
96). 0.32 g of a white solid is obtained after evaporation, (E) N- [4- [1- (5, 6,7,7, 8-tetrahydro-5, 5, 8, 8-) chloride tetramethyl-2-naphthalenyl) -2-propenyl] phenyl] -2,2,2-trifluoroacétimidoyle (Yd = 77 ~).
~, N ~ cF3 F (C) = 60.

WO 97/26237 PCT / F ~ 97 ~ 00079 1 H NMR 200MHz (CDC13): 1.30 and 1.31 (2s, 12H, 5,5,8,8-CH3); 1.50 (s, 4H, 6.7-CH2-); 2.31 (s, 3H, Me vinyl); 6.87 (s, 1H, vinyl H); 7, lQ-7.20 (m, 3H, ArH); 7.25-7.35 (m, 2H, ArH); 7.59 (d, 2H, ArH J 8.5 Hz).
RMN19F 50MHz (CDC13): -71.94 (s, 3F, CF3).
d) (~ 9-rl- (5,6,7,8-Tétrahydro-5,5,8,8-tetramethyl-2-n ~ pht ~ lenyl) -2-propenyllphenyl-5-trifluoro-methy] .- 1H-tetrazole (CB59741) We bring to 70 ~ C for 2 h, under atmosphere of argon and magnetic stirring, a solution of (E) N- [4-[1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] phenyl] -2,2,2-trifluoroacetimidoyl (0.32 g, 0.74 mmol), sodium azide (0.10 g, 1.48 mmol) in 1.5 ml of glacial acetic acid. After the reaction medium, the solvent is evaporated, taken up in dichloromethane and incorporated on silica. We purify by flash chromatography on silica (eluent ether: ether petroleum = 7: 93). After evaporation of the solvents, we obtains 0.30 g of a colorless oil, the (E) 1- [4- [1-(S, 6, 7, 8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] phenyl] -5-trifluoromethyl-1H-tetrazole (CB59741) (Yield = - 92 ~).
N - N

1 H NMR 200MHz (CDC13): 1.30 and 1.31 (2s, 12H, 5,5,8,8-CH3); 1.70 (s, 4H, 6.7-CH2-); 2.34 (s, 3H, Me vinyl); 6.91 (s, 1H, vinyl H); 7.16 (dd, 1H, ArH J
1.9Hz J 8, 1Hz); 7.27-7.37 (m, 2H, ArH); 7.47 (d, 2H, ArH J
8.6Hz !; 7.72 (d, 2H, ArH J 8.6 Hz).
RMN19F 50MHz (CDC13): --60.39 (s, 3F, CE'3).
MS EI 70 eV (m / z,% intensity): 440 (M, 100%);
397 (100); 343 (15); 248 (36); 215 (46); 111 (24); 69 (57).

WO 97/26237 PCT ~ FR97 / 00079 _ 150 MSHR EI 70 eV: Mtr = 490.2180 for C25H27N4F3 Mth = 440.2188 HPLC: Wate ~ s HR Cl8 column, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 90: 10 + 0.1% TFA, tetrazole (CB59741) tr =
3.88 min purity 96.6% i impurity tr = 3.24 min 2.7%.

Example 29: Preparation of (Z) 1- ~ 9- ~ 1- (5 6,7,8-Tetrahydro-5,5 8,8-tetramethyl-2-naphthalenyl) -2-propenyll-phenyll-5-txifluoromethyl-1H-tetrazole (CB29830) a) (Z) 4- ~ 1- (5,6 7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenylaniline.
A suspension of (Z) N- (carbethoxy) -4- [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] aniline (CB96682) (0.28 g, 1.28 mmol) in lON soda (3.84 ml, 38.4 mmol) and 1.5 ml of ethanol is brought to 80 ~ C for 3 h under an argon atmosphere and magnetic agitation. After cooling, it is extracted with dichloromethane (9 x 25 ml), dry over MgSO4, filter and evaporates to obtain 0.22 g of a crude orange oil, the (Z) q- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl ~ aniline (gross yield = 96.5 ~).
~ N ~

RMN1H 200MHz (CDC13): 1.04 e ~ 1.20 (2s, 12H, 5,5,8,8-CH3); 1.59 (s, 4H, 6.7-CH2-); 2.14 ~ d, 3H, Me vinyl J 1.4 Hz); 3.62 (br s, 2H, -NH2-); 6.32 (s, 1H, H vinyl); 6.72 (dm, 2H, ArH J 8.9 Hz); 6.78 (dd, 1H, ArH
J 1.8Hz J 8.2Hz) i 6.93 (d, 1H, ArH ~ 1.8Hz); 7.01 (dm, 2H, ArH J 8.4Hz) i 7.05 (d, 1H, ArH J 8.2Hz).

W 097 ~ Z623 ~ 7 PCTA ~ R97 / 00079 b) (Z) N- (Trifluoroacetyl) -9-il- (5,6,7,8-tet ~ hydrQ-5 ~ 5, 8, 8-tetramethyl-2-naph ~ alenyl) -2 propenyll-anlllne.
Mixing for 30 min at a ~ biante temperature, S under an argon atmosphere, a solution of (Z) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -aniline (0.22 g, 0.69 mmol) and 2-(trifluoroacetoxy) pyridine (0.11 ml, 0.76 mmol) in 2.5 ml anhydrous ether. The ethereal phase is then washed with water distilled, dried over MgSO4, filtered and evaporated. We take back with ether and incorporated on silica to purify by flash chromatography on silica (eluent ether: ether oil 7: 93). After evaporation of the solvents 0.20 g of a colorless oil, (Z) N- (trifluoroacetyl) -4-1 ~ [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] aniline (Yield = 70 ~).
F3C ~ ~ ~

RMN1H 200MH ~ (CDCl3): 1.00 and 1.20 (2s, 12H, 5, 5, 8, 8-CH3); 1.58 (s, 4H, 6.7-CH2-); 2.16 (d, 3H, Me vinyl J 1.4 Hz); 6.43 (s, 1H, vinyl H); 6.73 (dd, 1H, P ~ rH J 1.8Hz ~ 8.2Hz); 6.85 (d, 1H ArH J 1.8Hz); 7.05 (d, 1H, ArH J 8, 2Hz); 7.23 (dm, 2H, ArH J 8.6 Hz); 7.49 (dm, 2H, ArH J 8, 6Hz); 7.92 ~ s wide, 1H, -NH-).
RMN19F 50MHz (CDCl3): --76, 15 (s, 3F, CF3).
2 ~ c) Chloride of (Z) N- r4- rl- (5, 6, 7 8-tétr ~ hydro-5, 5, 8 8-tet ~ methyl-2-naphthalenyl) -2-propenyllphenyl-2.2 2-trifluoroac t ~ m; doyle A solution of (Z) N- (trifluoroacetyl) -4- [1-(5, 6, 7, 8-tetrahydro-5,5, 8, 8-tetramethyl-2-naphthalenyl) -2 -propenyl] aniline (0.20 g, 0.48 mmol), of triphenylphosphine CA 02243295 l998-07-l3 W 097/26237 PCT ~ R97 / 00079 _ 152 (0.30 g, 1.15 mmol) in 3 ml of carbon tetrachloride anhydrous is brought to reflux for 18 h under atmosphere of argon and magnetic agitation. After cooling, we evaporates the solvent, takes up in dichloromethane and incorporates on silica. The crude product is purified by chromatography flash on silica (eluent pure petroleum ether ~. We obtain after evaporation 0.16 g of a white solid, the chloride of N- [4 - [(Z) -1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthalenyl) -2-propenyl] phenyl ~ -2,2,2-trifluoroacetimidoyl (Yield = 77r ~).
F 3C ~ N
~, ~

F (C) = 76.
RMN1H 200MHz (CDC13): 0.96 and 1.18 (2s, 12H, 5, 5, 8, 8-CH3); 1.55 (s, 4H, 6.7-CH2-); 2.17 (d, 3H, Me vinyl J 1.4 Hz); 6.43 (s, 1H, vinyl H); 6.76 (dd, 1H, ArH J 1, 9Hz J 8, 1Hz); 6.84 (d, 1H ArH J 1.9Hz); 7.00--7.15 (m, 3H, ArH); 7.27 (dm, 2H, ArH J 8, 6Hz).
RMN19F 50MHz (CDC13): -72.01 (s, 3F, CF3).
d) (Z) 1- ~ 4- ~ 1- (5. 6 7. 8-Tetrahydro-5 5 8, 8-tetramethyl-2-naphthalenyl) -2-pro ~ enyll ~ hényll-5-trifluoro-1-methyl-tet ~ zole (CB29830) We bring to 70 ~ C for 20 h, under atmosphere of argon and magnetic stirring, a solution of (Z) N- [4-[1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] phenyl] -2,2,2-trifluoroacetimidoyl (0.16 g, 0.37 mmol), sodium azide (0.05 g, 1.74 mmol) in 0.75 ml of glacial acetic acid. After the reaction medium, the solvent is evaporated, taken up in dichloromethane and incorporated on silica. We purify by flash chromatography on silica (eluent ether: ether petroleum = 4: 96). After evaporation of the solvents, we CA 02243295 l998-07-l3 W O97 / 26237 PCTnFR97 ~ 0079 _ 153 0.07 g of a white solid is obtained, the (Z) 1- [4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -phenyl] -5-trifluoromethyl-1H- ~ etrazole (CB29830) (Yd =
43%).
_ CF3 NOT
~ N

F (~ C) = 111.
1 H NMR 200MHz (CDC13): 0.97 and 1.20 (2s, 12H, 5,5,8,8 - CH3); 1.57 (s, 4H, 6.7 - CH2 -); 2.22 (d, 3H, Me vinyl J 1.4 Hz); 6.54 (s, 1H, vinyl H); 6.76 (dd, 1H, PrH J 1.7Hz J 8, 1Hz); 6.83 (d, 1H, ArH J 1.7 Hz); 7.10 (d, 1H, ArH J 8, 1Hz); 7.42 (m, 4H, ArH).
RMN19F 50MHz (CDC13): -60.32 (s, 3F, CF3).
MS EI 70 eV (m / z,% intensity): 440 (M ', 100 96);
397 (63); 248 (9); 69 (33).
MSHR EI 70 eV: Mr = 440.2173 for C25H27N4F3 M; h =
440.2188 HPLC: Waters HR column C ~ 8, 8 ~ 100 mm, 6 ~, VV Waters 486 detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 90: 10 + 0.1% TFA, tetrazole (CB29830) tr =
3.37 min purity 98.7 ~; impurity tr = 4.05 min 0.8%.

F. Example 30: Preparation of ~ cide (Z) 2-rl-(5 6,7.8-tetrahy ~ ro-5 5 8,8-tet ~ methyl-2-naphth ~ lenyl) -2-propenyllthienyl-5-phos-phonique (CB46802) a) (F.) and (Z) 2- ~ 1- (5 6 7 8-Tetrahydro-5 5.8 8-tetramethyl-2-n ~ pht ~ lenyl) -2-propenyll ~ hienyl-5-diethyl phosphon ~ your.

CA 0224329 ~ 1998-07-13 WO 97/26237 PCTA ~ R97 / 00079 _ 154 We bring to re ~ lux for 15 h, under atmosphere of argon and magnetic stirring, a suspension of (Z) 2-[1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -5-bromothiophene (2.52 g, 6.47 mmol), diethylphosphite (1.67 ml, 12.99 mmol), triethylamine (1.80 ml, 12.94 mmol), tetrakis (triphenylphosphine) palladium (0.87 g, 0.75 mmol) in 3 ml of anhydrous THF.
After re ~ stiffening of the reaction medium, we resume at ethyl acetate (100 ml) and washed with HCl solution lN then with a saturated NaCl solution. After evaporation solvent, the crude product is purified by chromatography flash on silica (eluent ether: petroleum ether = 50:
50 then 70: 30). 0.83 g of a yellowish oil (yield = 29%) composed of a mixture of (E) and (Z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] thienyl-5-diethyl phosphonates (proportion (E): (Z) = 75: 25 by H NMR 80 MHz).
~ And 80MHz H NMR (CDCl3): 1.05-1.50 (m, 18H, 6Me);
1.55-1.70 (m, 4H, 6.7-CH2); 2.20 (s, 0.25x3H, vinyl Me isomer Z); 2.30 (s, 0.75 x 3 H, vinylic isomer E);
3.90-4.35 (m, 4H, -OCH2-); 6.50-7.65 (m, 6H, ArH and H
vinyl).
b) Acid (E) 2- ~ 1- (5,6 7,8-tetrahydro-5 5, ~, 8-2 ~ tetramethyl-2-naphthalenyl) -2-propenyllthienyl-5-phosphonic (CB46802) We add to the ~ syringe of bromotrimethylsilane (1.58 ml, 11.97 mmol) on a suspension of the mixture of (E) and (Z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -diethyl thienyl-5-phosphonates (0.83 g, 1.86 mmoI) in 12 ml of acetonitrile. It is brought to reflux for 2 h, under magnetic agitation and argon atmosphere, the middle WO 9712623'7 PCT / F ~ 97/00079 reactive. After cooling, it is evaporated to dryness and reprencl with ethanol. We evaporate again and precipitate a white solid with a minimum of ethyl ether. We filter, dry to obtain 0.11 g of a white solid, the acid (~) 2-[1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] thienyl-5-phosphonic (CB46802) (Yield = 15 ~).
~ II ~ OH

F (~ C) = 175-176.
H NMR 200MHz (CDC13): 1.26 and 1.27 (2s, 12H, 5, S, 8.8-Me); 1.69 (s, 4H, 6.7-CH2); 2.26 (d, 3H, Me vinyl J 0.9 Hz); 7.02 (s, 1H, vinyl H); 7.09 (dd, 1H, Ar ~ J 1.7Hz J 8.6Hz); 7.15-7.35 (m, 4H, ArH); 7.45 (dd, 1H, ArH J = 3.7H2 ~ = 8.6Hz).
MS EI 70 eV (m / z, ~; intensity): 390 (M, 0, l91i);
375 (0.4%); 310 (87), 295 (100); 262 (35); 183 (27).
HPLC: Waters HR C18 column, 8 x 100 mm, 6 ~, UV waters 486 detector at 280 nm, flow rate 3 ml / min, eluent MeOH: H ~ O = 85: 15 + 0.1% TFA, acid (CB46802) tr =
2.93 min 98.8%; impurity tr = 1.36 min 0.7%.
~ xample 31: Preparation of acid ~ Z) 4- ~ 1-(5.6,7.8-tetrahydro-5,5,8.8-tetramethyl-2-naphthalenyl) -1-(phenyL) -2-ethenyll ben ~ oï ~ eu (CB59892).

1) (Z) 4- ~ 1- (5.6.7.8-Tétrahydro-5.5.8,8-tet ~ methyl-2-naphthalenyl) -1- (phenyl) -2-ethenyllbenzonitrile.
To a solution of (Z) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] -bromobenzene (2.21 g, 4.96 mmol) in 18.5 ml of DMF
anhydrous, the cyanide of copper (0.52 g, 5.81 mmol). The reaction medium is carried at reflux for 15 h. After returning to room temperature, CA 02243295 l998-07-l3 WO 97/26237 PCT ~ FR97 / 00079 , the reaction medium is diluted with ether (200 ml) and filtered on celite. The organic phase is washed with a saturated NaHCO3 aqueous solution (3 x 50 ml) then dry on MgSO4, filter and evaporate. ~ e raw product is purified by flash chromatography on silica (eluent ether of petroleum: ether = 100: 2). 1.29 g of = oil are obtained yellowish, the (Z) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] benzonitrile (Yield = 66%).
NC ~

~
1 H NMR 200 MHz (CDC13): 1.05 and 1.35 (2s, 12H, 5.5.8.8 Me); 1.65 (s, 4H, 6.7-CH2-); 6.80-6.90 (m, 2H, H
vinyl and ArH); 7.00-7.10 (m, 3H, ArH); 7.20-7.50 (m, 8H, ArH).
2) Acid (Z) 4- ~ 1- (5 6 7 8-tetrahydro-5,5 8 8-tetramethyl-2-naphthalenyl) -1- (~ hényl) -2-éthenyllbenzolFque (C ~ 59892).
A suspension of (Z) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2- = ~
ethenyl] benzonitrile (0.50 g, 1.27 mmol) dissolved in potash (1.4 g, 25 mmol) hydroethanolic (H2O 1.8 ml and EtOH 17.5 ml) is heated to reflux with stirring magnetic for 48 h. The ethanol is evaporated at the rotary evaporator, takes up in water ~ 10 ml), acidifies with 3N HCl, extracted with ethyl ether (3 x 50ml), dry the ethereal phase on MgSO4, filters and evaporates. The product is washed with pentane, filtered and dried. We obtain 521 mg r of a white solid, acid (Z) 4- [1- (5,6,7,8-tetrahvdro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-:
ethenyl] benzoic (CB59892) (Yd = 63 ~ 3.

WO 97/2623, PCT ~ R97 / 00079 _ 157 HOOC
- W ~ ' - ~ 3 F (~ C) = 222.
IR (cm): 2954i 1676; 1604; 1416; 1289.
RMN1H 200MHz (CDCl3): 1.03 and 1.20 (2s, 12H, 5.5.8.8 Me); 1.65 (s, 4H, 6.7-CH2-); 6.85 (dd, 1H, J 2Hz and J 8Hz); 6.92 (s, 1H vinyl); 7.04-7.08 (m, 3H, ArH);
7.21-7.39 (m, 6H, ArH); 7.82 (d, 2H, ~ 8Hz).
MS EI 70eV (m / z,% intensity): 410 (M, 100%);
395 (48).
MSHR EI 70 eV: M r = 41Q, 2246 for C29H30O2 M ~ h =
410.224 ~.
HPLC Water Column ~ HR C18, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 90: 10 + 0.1 ~ TFA, acid (CB59892) tr =
5.34 min 99.8 ~.

Example 3 ~: Preparation of (Z) 5- ~ 9- ~ 1- (5.6,7,8-~ extr ~ hydro-5.5 8.8-tetramethyl-2-naphthalenyl) -1- (phenyl) - ~ -ethenyl'lphenyll-1H-tetrazole (CB96561).
To a solution of (Z) 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] -benzonitrile (0.35 g, 0.89 mmol) in anhydrous toluene (1.8 ml), is successively added dibutyltin (22.8 mg, 0.09 mmol) and azide trimethylsilyl (0.235 ml, 1.78 mmol). The middle reactiGnnel is heated for 18 h at reflux (110 ~ C) under argon atmosphere and magnetic agitation. We purify by flash chromatography on silica (eluent MeOH: CH2C12 = 5 : 95) to obtain 260 mg of a powder after evaporation white, the (Z) 5- [4- [1- (5,6,7,8-tetrahydro-5,5,8,8-~ CA 02243295 1998-07-13 WO 97/26237 PCT ~ FR97 / 00079 _ 158 ~

tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyl] phenyl ~ -lH-tetrazole (CB96561) (Yield = 67%) ~.
NOT
NOT
~ ', ~ 3 F (~ C) = 282.
IR (cm): 2958; 1604; 1496; 1446; 1060; .880.
RMN1H 200MHz (CDCl3): 1.03 and 1.26 (2s, 12H, 5,5,8,8-Me); 1.63 (s, 4H, 6.7-CH2-); 6.88-6.90 (m, 2H);
7.08-7.35 (m, 9H, ArH); 7.79 (d, 2H, ArH, ~ 8Hz).
MS EI 70eV (m / z,% intensity): 439 (M, 62 ~);
406 (100); 209 (65); 178 (13).
MSHR EI 70 eV: Mtr = 43g, 2484 for C29H30N ~ M ~
434.2470.
HPLC Column Waters HR Cl8, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 90: 10 + 0.1% TFA, tetrazole (CB96561) tr =
3.69 min 99.7%.

Example 33: Preparation of (E) 5- ~ 4- ~ 1- (5.6 7.8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1- (phenyl) -2-ethenyllphenyll-1H-tetrazole (CBS6898).
To a solution of (E) 4- ~ 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-phenyl-2-ét ~ enyl] -benzonltrile (0.29 g, 0.74 mmol) in anhydrous toluene (1.5 ml), successively adding dibutyltin (23.3 mg, 0.089 mmol) and azide trimethylsilyl (0.200 ml, 1.48 mmol). The middle reaction is heated 15 h at reflux (110 ~ C) under argon atmosphere and magnetic agitation. We purify by flash chromatography on silica (eluent MeOH: CH2C12 = 5 : 95) to obtain after evaporation 40 mg of a powder WO 97/26237 PCT ~ FR97 / 00079 white, 5- [4 - [(E) -1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl.-2-naphthalenyl) -1- (phenyl) -2-ethenyl] phenyl] -lH-t é trazole (CB 5 6 8 9 8) (R dt 12%).

¦ N

~ H

F (~ C) = 254.
IR (cm): 2958; 1666; 1610; 1496; 1456; 1404; 1362; 1 ~ 72; 1056; .878 1 H NMR 20 ~ M ~ z (CDCl ~): 1.22 ~ and 1.26 (2s, 12H, 5,5,8,8-Me); 1.67 (s, 4H, 6.7-CH2-); 6.95 (s, 1H, vinyl); 7.14 (dd, 1H, ArH, J 2Hz and J 8Hz); 7.21 (m, 9H, ArH '; 7.78 (d, 2H, ArH, J 8Hz).
MS EI 70ev (m / z,% intensity): 434 (M, 66 ~);
406 (100); 219 (39); 204 (57).
MSHR EI 70 ev: M, = 434.2473 for C ~ gH3,, N ~ M ~ h =
434.2470.
HPLC Column Waters HR Cl8, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: l ~ 2O = 90: 10 + 0.1 ~ of TFA, tetrazole (CB56898) tr = 4.17 min 99.4 ~

F. example 34: Preparation of (F.) and (Z) 5-r2-rl-(5.6 7 8-tetrahydro-5.5 8.8-tetramethyl-2-naphthalenyl) -2-propenyl) l-5-thienyll-1H-tetrazoles ~ CB07739 and CB92855).
'' 1) (F) and (Z) 2-rl- ~ 5 6,7,8-tétrahydro-5.5 8.8-tetr ~ methyl-2-naphthalenyl) -2-propenyl) l-5-cyanothiophenes.
To a bromide solution of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -6-methyltrlphenyl-phosphonium (7.28 g, 13.22 mmol) in 20 ml of THF, we add at -70 ~ C a solution of tBuOK 1M in THF (14 _ 160 ml, 14 mmol). Stirring is continued at -70 ~ C for 1 h before adding 2-acetyl-5-cyanothiophene (1 g, 6.61 mmol) dissolved in 10 ml of THF. The middle reaction is brought to room temperature and stirred S for 2 p.m. Then hydrolyzed at 0 ~ C with a solution of 3N HCl. After returning to room temperature, extract with ether, dry over MgSOq, filter and evaporate the solvents.
The crude product is purified by flash chromatography on silica (eluent petroleum ether = ethyl ether 100: 1).
~ 0.41 g of a yellow oil is obtained, the (Z) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)) -5-cyanothiophene and 0.39 g of a white powder, the (E) 2-[1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-nap ~ talenyl) -2-propenyl)] - 5-cyanothiophene and 0.70 g of the mixture of the two IS isomers (Z) and (E) (overall yield = 68 ~).
Isome ~ e (Z):
NC ~

RMN1H 200MHz (CDCl3): 1.10 and 1.25 (2s, 12H, 5,5,8,8-Me); 1.67 (s, 4H, 6.7-CH2); 2.20 ~ s, 3 ~, Me vinyl); 6.65 (s, 1H, vinyl H); 6.90 (d, 2H, ArH, J
4Hz); 7.05 (s, 1H, ArH); 7.22 (d, 2H, ArH, J 8Hz); 7.40 (d, 1H, ArH, J 4H ~).
Isomer (E):

--CN

2 ~ F ~~ C) = 108.
1 H NMR 200 MHz (CDCl3): 1.30 (s, 12H, 5,5,8,8-Me);
1.70 (s, 4H, 6.7-CH2); 2.30 (s, 3H, vinyl Me); 7.02 (s, WO 97S2623'7 PCTJ1 ~ 97/00079 1H, vinyl H); 7.10-7.20 (m, 2H, ArH); 7.25-7.35 (m, 2H, ArH); 7.55 (d, 1H, ArH, J 4Hz).
.
2) (E) 5- ~ 2-rl- (5,6,7,8-tetrahydro-5,5,8,8-5 tetramethvl-2-naphthalenyl) -2- ~ ropenyl) 1-5-thienyll-1H-tetrazole (CB07734).
To a solution of (E) 2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] - 5-cyanothiophene (0.39 g, 1.16 mmol) in anhydrous toluene10 (2.3 ml), gold, successively add oxide dibutyltin (38.3 mg, 0.14 mmol) and acetate trimethylsilyl (0.31 ml, 2.32 mmol). The reaction medium is chcu ~ fé 14 ha reflux (110 ~ C) under an argon atmosphere et agi ~ ation magnétlque. Purify by chromatography flash on silica (eluent MeOH: CH2C12 = 10: 90) for obtain after evaporation 118.8 mg of a white powder, the (E) 5 - [2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] - 5-thienyl] -1H-tetrazole (CB07734) (Yid = 27 ~).

F (~ C) = 186--189.
IR (cm): 3644; 3272; 1594; 1458; 1406.
1 H NMR 200 MHz (CDCl3): 1.27 and 1.28 (2s, 12H, 5,5,8,8-Me); 1.67 (s, 4H, 6.7-CH2-); 2.28 (s, 3H, Me vinyl); 7.02 (s, 1H, vinyl H); 7.08-7.15 (m, 2H, ArH); 1.24-7.30 tm, 2H, ArH) i 7.74 (d, 1H, ArH, J 4Hz).
MS ~ I 70eV (m / z, ~ intensity): 378 (M, 100%);
358 (83); 69 (67).
MSHR EI 70 eV: Mtr = 378.1880 for C22H2 ~ N4S Mt ~ =
378.1878.
HPLC Column Waters HR Cl8, 8 x 100 mm, 6m, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent W097 / 26237 PCT ~ 7/00079 MeOH: H2O = 90: 10 + 0.1 ~ TFA, tetrazole (CB ~ 7734) tr =
3.49 min 98.9%.

3) (Z) 5-r2-rl-15 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl ~ l-5-thienyll-1 ~ -tétr ~ zole (CB92855).
To a solution of (Z) 2 - [(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] -5-cyanothiophene (0.41 g, 1.22 mmol1 in anhydrous toluene (2.4 ml), successively adding dibutyltin (39.2 mg, 0.15 mmol) and azide trimethylsilyl (0.325 ml, 2.44 mmol). The middle reaction is heated 15 -h at re ~ ux (110 ~ C) under argon atmosphere and magnetic agitation. We purify by flash chromatography on silica (eluent MeOH: CH2C12 = 5 : 95) followed by a preparative HPLC (eluent MeOH: H2O = 92 : 8 ~ 0.1% TFA) to obtain 192.6 mg after evaporation of a white powder, the (Z) 5- [2- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl)] - 5-thienyl] -1H-tetrazole (CB92855) (Yield = 42%).

'NH ~
= ~
F (~ C) = 126 ~
IR (cm): 2950; 1552; 1460; 1408; 1362.
1 H NMR 200MHz (CDCl3): 1.07 and 1.20 (2s, 12H, 2 ~ 5,5,8,8-Me); 1.58 (s, 4H, 6.7-CH2-); 2.22 (s, 3H, Me vinyl); 6.56 (s, 1H, vinyl H) i 6.88-7.09 (m, 2H, ArH); 7.10-7.16 (m, 2H, ArH); 7.66 ~ d, 1H, ArH, ~ 4Hz).
MS EI 70eV (m / z,% intensity): 378 (M, 86%);
350 (74%); 319 (11 ~); 165 (15%); 69 (100 ~).
MSHR EI 70 eV: Mtr = 378.1889 for C22H26N4S Mth =
378.1878 t WO 97/26237 PCT ~ R97 ~ 0079 HPLC Column Waters HR C18, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 90: 10 + 0.1% TFA, tetrazole (CB07734) tr =
2.87 min 98.9%.
S
~ xample 35: Pre ~ aration of the acid (~) 5-rl-(5.6 7.8-tetrahydro-5.5 8 8-tetramethyl-2-naphthalenyl) -2-pro ~ enyllpyridinyl-2-carboxylic (CB16279).
A suspension of (Z) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-methyl carboxylate, (0.3 g, 0.82 mmol) in solution in potassium hydroxide (0.46 g, 2.18 mmol) hydromethanol (H2O 1.1 ml and MeOH 9 ml) is heated to reflux with stirring magnetic for 3 h. The methanol is evaporated a the rotary evaporator, take up in water (10 ml), acidify with 3N HCl, extract (5 x 30ml) with dichloromethane, dry it ethereal phase on MgSO4, filter and evaporate. The gross product is washed with pentane and then filtered, 0.28 g of a white solid, acid (Z) 5- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-carboxylic (CB16279) (Yield = 98 ~).
HOOC

F (~ C) = 62-64.
IR (cm): 3250; 2954; 1898; 1706; 1590.
RMN1H 200MHz (CDC13): 0.94 and 1.19 (2s, 12H, 5,5,8,8-Me); 1.56 (s, 4H, 6.7-CH ~ -); 2.23 (d, 3H, Me vinyl, 3 1.3 Hz); 6.67 (m, 1H, vinyl H); 6.73 (s, 2H, ArEl); 7.09 (d, 1H, ArH, J 8Hz); 7.82 (d, 1H, ArH, J
8Hz); 8.15 (d, 1H, ArH, J 8Hz) i 8.41 (s, 1H, ArH).
MS EI 70 eV (m / z, ~ intensity): 349 (M, 76%);
334 (100); 316 (5).

WO 97/26237 PCT ~ FR97 / 00079 1 ~ 4 .

MSHR EI 70 eV: M ~ = 399.2059 for C23H27NO2 Mth =
349.2042.
HPLC Column Waters HR Cl8, 8 x 10Q mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent ~; MeOH: H2O = 90: 10 + 0.1% TFA, acid (CBl6279) tr 5.86 min 99.7%.

F.xem ~ le 36: Preparation of acids (E) and (Z) 2-~ 1- (5,6,7. ~ -Tétrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyllpyri-dinvl-5-carbQxyliques (CB9Q525) and (CB93634).

1) (E) and (Z) 2-rl- (S, 6,7,8-Tétrahydro-3,5, S, 8 3-Dentamethyl-2-naphthalenyl) -2-propenyllpyridinyl-S-~ methyl arboxYlates.
To a bromide solution of (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -6-methyltriphenyl-phosphonium (5.28 g, 9.48 mmol) in 15 ml of THF, add at -70 ~ C a solution of tBuOK 1M in THF (10 ~ 0 ml, 10 mmol). Continue stirring at -70 ~ C for 45 min before adding a solution of 2-acetylpyridine-5-methyl carboxylate '(0.85 g, 4.74 mmol) in 7 ml of THF
at this temperature. The reaction medium is brought to room temperature and stirring is continued for 13 h. Then hydrolyzed at 0 ~ C with a 3N HCl solution (30 ml). After returning to ambient temperature, it is extracted with dichloromethane, dries over MgSO4, filters and evaporates the solvents. The crude product is purified by chromatography flash on silica (eluent petroleum ether: ether = 100:
10 then 100: 15). 0.59 g of esters (E) and (Z) are obtained 2- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-methyl naphthalenyl) -2-propenyl] pyridinyl-5-carboxylates (Yield = 34%) ((E): (Z) = 64: 34).
Isomer lZ):

WO 9 ~ 6 ~ 3'7 PCT / FRg7 / 00079 MeO2C ~ N

RMN1H 200MHz (CDCl3): 0.60 and 1.15 (2 s, 12H, 5,5,8,8-Me); 1.40-1.60 (m, 4H, 6.7-CH2-); 2.25 (s, 3H); 2.32 (s, 3H); 3.95 (s, 3H, MeO-); 6.60 (s, 1H); 6.75 (s, 1H);
7.05 (~, 1H, ArH); 7.62 (m, 1H, ArH); 7.92 (dd, 1H, ArH, J
2Hz and J 8H ~); 9.15-9.25 (m, 1H, ArH).
Isomer (F.) ~ ~ ~, CO2Me RMN1H 200MHz (CDCl3): l, 30 and l, 32 (2 s, 12H, 5,5,8,8-Me); 1.40 (s, 4H, 6.7-CH ~ -); 2.27 (s, 3H); 2.32 (s, 3H); 3.97 (s, 3H, MeO-); 6.82 (s, 1H); 6.90 (s, 1H); 7.08 (s, 1H, ArH); 7.20 (m, 1H, ArH); 8.02 ~ dd, lH, ArH, J 2Hz and ~ 8Hz); 9.15-9.25 (m, 1H, ArH).

2) Aci ~ es (E) and (Z) 2- ~ 1- (5 6,7,8-tétrahydro-3,5,5,8 8-pen ~ amethyl-2-n ~ htalenyl) -2-propényllpyri- ~ inyl-Methyl 5-carhoxylates (CB90525 and CB93634).
A suspension of (E) and (Z) of 2- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-methyl propenyl ~ -pyridinyl-5-carboxylates ((Z): (E) =
64: 36)), (0.59 g, 1.56 mmol) dissolved in potassium hydroxide (0.87 g, 15.6 mmol) hydromethanol (H2O 2 ml and MeOH 17.6 ml) is heated to reflux with stirring magnetic for 3 h. The methanol is evaporated at the rotary evaporator, take up in water (10 ml), acidify with 3N HCl, extract (5 x 30ml) with dichloromethane, dry it WO 97/26237 PCT ~ FR97tO0079 16 ~

ethereal phase on MgSO4, filter and evaporate. The gross product is purified by preparative HPLC (eluent: MeOH: H2O: 86:
14), 138 mg of a white solid is obtained, acid (Z) 2-[1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-5-carboxylic (CB90525) (Yield = 25 ~) and 126 mg. of a white solid, acid (E) 2-[1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-5-carboxylic (CB93634) (YId = 22%).

Acid (Z) 2- ~ 1- (5,6,7,8-tetrahydro-3,5,5,8 8-pentamethyl-2-naphthalenvl) -2- ~ ropényllpyridinvl-5-carboY ~ vlique (CB90525).
HOO C ~

F (~ C) = 85.
IR (cm ~): 2g56; 2866; 1722; 1898; 1602; 1450;
1390.
1 H NMR 200 MHz (CDCl;): 0.79 and 1.19 (2 s, 12 H, 5,5,8,8-Me); 1.23-1.51 (m, 4H, 6.7-CH2-); 2.27 (s, 3H); 2.37 (s, 3H); 6.51 (s, 1H); 6.95 (s, 1H); 7.02 (s, 1H, ArH);
7.16 (s, 1H); 8.30 (d, 1H, ArH, J 5Hz); 9.40 (s, 1H, ArH);
12.7 (s, 1H, mobile H).
MS negative 200 eV (m / z,% intensity): 363 (M, 67 ~); 362 (100).
HPLC Column Waters HR Cl8, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 85: 15 + 0.1% TFA, acid (CB90525) tr =
3.32 min 98.4%.

W 097/26237 P ~ 1 / ~ K ~ 7 ~ 0079 Acid (E) 2- rl- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl pyridinyl-5 c ~ rboxvlique (CB9363 ~).
OOOH

~ NJ

~; F (~ C) = 157.
IR (cm ~): 3106; 2956; 2595; 1734; 164 ~; 1600;
1440; 1392; 1242; 119 ~; 1142.
1 H NMR 200MH ~ (CDCl,): 1.27 e ~ 1.29 (2 s, 12H, 5,5,8,8-Me); 1.69 (s, 4H, 6.7-CH2-); 2.29 (s, 3H); 2.35 (s, 3H); 7.16 (s, 1H); 7.21 (s, 1H); 7.55 (m, 1H, mobile H);
7.65 (s, 1H); 7.92 (d, 1H, J 8Hz); 8.73 (d, 1H, J 8 Hz);
9.47 (s, 1H,).
MS IC negative 200 eV (m / z,% intensity): 363 (M, 84 ~); 362 (100).
1 ~; HPLC Column Waters HR Cl ~, 8 x 100 mm, 6 ~ 1, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 90: 10 + 0.196 TFA, acid (CB93634) tr =
4.72 min g 8.1%

~ xample 37: Preparation of acids (E) and (Z) 5-~ 1- (5,6,7,8-tee ~ rahydro-3,5,5,8,8- ~ entamethyl-2-naphthalenyl) -2-propenyllpvridinyl-2-carboxylic (C ~ 356004) and (CB71329).

1) (: ~;) and (Z) 5-rl- (5,6.7,8-tétrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyll pyridinyl-2- ~ N, N-~ 3; iso ~ ropyl) amides.
To a bromide solution of (5, 6,7,8,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -6-methyltriphenyl-phosphonium (11.1 g, 19.9 mmol) in 31 ml of THF, we add at -70 ~ C a solution of tBuOK 1M in THF (21 ml, 21 mmol). Stirring is continued at -70 ~ C for 1 h W 097/26237 PCT ~ R97 / 00079 16 ~
_ -before adding 5 - acetyl-2 - (N, N-diisopropyl) amide (2.47 g, 9.94 mmol) at this temperature. The reaction medium is brought to room temperature and the stirring is continued for 6 p.m. Then hydrolyzed at 0 ~ C with a solution 3N HCl (25 ml) ~ After returning to room temperature, dichloromethane extract, dried over MgSO4, filtered and evaporates the solvents. The crude product is purified by flash chromatography on silica (eluent petroleum ether ether = 100: 10 and 100: 20). 3.59 g of a yellowish gum, the (E) and (Z) 5- [1- (5, 6,7,7, 8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2- (N, N-diisopropyl) amides (overall yield = 83 ~) ((E): (Z) = 1 : 2) -lsomer (Z):
NiPr2 0 ~
N ~

~
1 H NMR 200 MHz (CDCl 3): 0.85 (s, 6H); 1.05--1.20 (m, 12H); 1.25 (s, 6H); 1.40-1.60 (m, 4H, 6.7-CH2); 2.20 (s, 3H); 2.25 (s, 3H); 3.35-3.65 m, 2H); 6.60 (s, 1H ~; 6, -65 (s, 1H); 7.00 (s, 1H); 7.30 (m, 1H); 7.45 (m, 1H); 8.25 (m, 2 ~) 1H).
Isomer (E) ~ NiPr2 ~ N.

1 H NMR 200 MHz (CDCl ~): 0.9 (s, 12H, 5,5,8,8 - Me);
1.05-1.20 (m, 12H); 1.30 (s, 4H, 6.7-CH2); 2.17 (s, 3H);
2.22 (s, 3H); 3.70--3.95 (m, 2H); 6.92 (m, 1H); 7.10 (m, W 097 / 2623'7 PCT ~ R97 / 00079 _ 16 ~

1H); 7.20 (m, 1H); 7.50 (m, 1H); 7.80-7.90 (m, 1H); 8.45 (m, 1H).

2) (E) and (Z) 5-rl- (5,6,7,8-tétrahydro-3,5,5,8,8-S ~ entamethyl-2-naphthalenyl) -2-propenyll-2-formyl pyridines.
To a solution of (E) and (Z) 5- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] -pyridinyl-2- (N, N-diisopropyl) amides ((E): (Z) =
1: 2) (2.56 g, 5.86 mmol) in 28 ml of THF, added to -70 ~ C 1.5 M diisobutylaluminum hydride solution in toluene (15.9 ml, 8.8 mmol). We let go back to room temperature and stirred at this temperature for 2 h. Cool to -70 ~ C and hydrolyze with a solution aqueous 3N HCl (25 ml), rise to temperature ambient and extracted with dichloromethane (5 x 50 ml). The organic phase is dried over MgSO4, filtered and evaporated.
The crude product is purified by flash chromatography on silica (eluent petroleum ether: ether = 100: 10). We obtain ~ 0.57 g of a yellow oil, the (E) and (Z) 5- [l-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] -2- ~ ormylpyridines (Yield = 28 ~) (E: Z = l: 1).
CHO
~ N

1 H NMR 200 MHz (CDCl3): 0.76 (s, 0, Sx6H ~; 1.20 (s, o, 5x6H); 1.28 (s, 0.5x12H); 1.40-1.60 (m, 0.5x4H); 1.68 (s, 0.5x4H); 2.15-2.30 (m, 6H); 6.51 (s, 0.5xlH ~; 6.72 (s, 0.5xlH); 6.95-7.05 (m, 1H) i 7.14 (s, 0.5xlH); 7.18 (s, 0.5xlH); 7.55-7.70 (m, 0.5x1H); 7.80 (d, 0.5xlH, J 8Hz);
7.96 (m, 1H); 8.45 (m, 0.5 x 1 H); 8.95 (m, 0.5 x 1 H); 9.96 (s, 0.5xlHI; 10.08 (s, 0.5 x 1 H).

CA 02243295 l998-07-l3 WO 97/26237 PCTAFR97 / 0007g 3) (E) and (Z) 5-rl - (5, 6,7,8 - tetrahydro-35 5,8,8--pentamethyl-2-naphthalenyl) -2-propenyllpyridinyl-2-methyl carboxylates.
To a solution of the mixture of (E) and (Z) 5 - [1--(5r6.7 ~ 8-tetrahydro-3,5 ~ 5 ~ 8,8-pentamethyl-2-naphthalenyl) -2-propenyl] -2 - formylpyridines (0.57 g, 1.64 mmol) in 41 ml of methanol, 0.145 ml of acid are successively added acetic acid, manganese oxide (1.43 g, 16.5 mmol) and sodium cyanide (0.40 g, 8.20 mmol) at temperature ambient. The reaction medium is stirred at this temperature for 4 h. We filter on paper, evaporate and taken up in 20 ml of water, extracted with ether (5 x 50 ml), dries on MgSO4, filters and evaporates. The gross product is ~
purified by flash chromatography on silica (eluent ether ether oil = 70:30). We obtain after evaporation 0.11 g of a yellow paste, the (Z) 5- [1- (5, 6,7,8,8-tetra ~ ydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-Methyl 2-carboxylate (Yd = 18 ~) and 0.09 g of a white powder, the (E) 5- [1- (5, 6,7,8 - tetrahydro-3,5,5,8, B-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-methyl carboxylate (Yield = 14 9 ~).
Isomer (Z):
MeO2C ~
N ~

1 H NMR 200 MHz (CDCl3): 0.78 and 1.18 (s, = 6 H, 5,5,8,8-Me); 1.40-1.65 (m, 4H, 6.7-CH2-); 2.21 (s, 3H, Armed); 2.24 (s, 3H, Me vinyli ~ ue); 3.94 (s, 3H, -OMe); 6.52 (s, 1H); 6.67 (s, 1H); 6.98 (s, 1H, ArH); 7.55-7.59 (m, 1H, ArH); 7.94 (d, 1H, ArH J 7Hz); 8.38 (m, 1H, ArH).
Isomer (F.) WO 97126237 PCT ~ FR97 / 00079 .

F (~ C) = 132.
1 H NMR 200 MHz (CDCl3): 1.27 (S, 12H, 5,5,8,8-Me);
1.68 (s, 4H, 6.7-CH2-); 2.20 (s, 3H, vinyl Me); 2.23 (s, S 3H, ArMe); 4.00 (s, 3H, -OMe); 6.99 (s, 1H) i 7.12 (s, 1H);
(m, 2H, ArH); 7.18 (s, 1H); 7.89-7.94 (m, 1H, ArH); 8.11 (d, 1H, ArH, ~ 8Hz); 8.89 (m, 1H, ArH).

4) Acid (Z) 5-rl- (5 6,7,8-tetrahydro-3,5 5,8,8-pentamethyl-2-na ~ htalenyl) -2-propényllpyridinyl- ~ -carboxylic (CB56004).
A suspension of (Z) 5- ~ 1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-Methyl 2-carboxylate, (110 mg, 0.29 mmol) in solution 1 ~ in potash (160 mg, 2.90 mmol) hydromethanol (H2O 0 ~ 3 ml and MeOH 3.1 ml) is heated to reflux under magnetic stirring for 6 h. The methanol is evaporated at the rotary evaporator, take up in water (10 ml.), acidify with 3N HCl, extract (3 x 20ml) with dichloromethane, dry it ethereal phase on MgSO4, filter and evaporate. The product ~ rut is washed with pentane and then filtered, 80 mg of a solid, acid (Z) 5- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl ~ pyridinyl-2-carboxylic (CB56004) (Yield = 76 ~).
HOOC
NOT

'25 F (~ C) = 66.

W 097/26237 PCTnFR97 / 00079 _ 172 IR (cm l): 3250; 2924; 1705; 1590; 1446i 1282;
1240; 1150; 1030 1 H NMR 200M ~ z (CDCl3): 0.75 and 1.20 (2s, 12H, 5,5,8,8-Me); 1.23 (s, 3H, vinyl Me); 1.50-1.56 (m, 4H, 6.7-CH2-); 2.26 (s, 3H, ArMe); 6.48 (s, 1H); 6.73 (s, 1H);
7.03 (s, 1H); 7.96 (dd, 1H, ArH, J 1.7 Hz and J 8 Hz); 8.05 (d, 1H, ArH J 8 Hz); 8.24 (s, 1H, ArH).
MS EI 70 eV (m / z,% intensity): 363 (M, 70%);
348 (100); 330 (35).
MSHR EI 70 eV: Mtr = 363.22 ~ 1 for C2 ~ H29NO, Mth =
363.2198 HPLC Column Waters HR Cl8, 8 x 100 mm, - = 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 85: 15 ~ 0.1% TFA, acid (CB56004) tr =
3.22 min 97.3%

5) Acid (E) 5-rl- (5 6,7,8-tetrahydro-3,5 5 8,8-pentamethyl-2-naphthalenyl) -2-propenyllpyridinyl-2-c ~ rboxyllque (CB71329) A suspension of (E) 5- [l- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-Methyl 2-carboxylate, (90 mg, 0.23 mmol) in solution in potash (130 mg, 2.30 mmol) hydromethanol ~ H2O 0.25 ml and MeOH 2.5 ml) is heated to reflux under 2 ~ magnetic stirring for 2 h. The methanol is evaporated a the rotary evaporator, take up in water (10 ml), acidify with 3N HCl, extract (3 x 20ml) with dichloromethane, dry it ethereal phase on MgSO4, filter and evaporate. The gross product is washed with pentane and then filtered, 80 mg of a white solid, acid ~ E) S- ~ 1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) -2-propenyl] pyridinyl-2-carboxylic (CB71329) (Yield = 95%).

CA 02243295 l998-07-l3 W 097 / 2623'7 PCTAFR97 / 00079 .

~ COOH

F (~ C) = 172 IR (cm): 3406; 2924; 2458; 1894; 1710; 1584;
1452; 1320; 1128; 1132.
1 H NMR 200 MHz (CDCl 3): 1.27 (s, 12H, 5.5, 8.8 - Me);
1.68 (s, 4H, 6.7-CH2-); 2.21 (s, 3H); 2.24 (s, 3H); 6.98 (s, 1H, H ~ inylic) i 7.13 (s, 1H, ArH ~; 7.17 (s, 1H); 8.03 (d, 1H, ArE ~, J 8 Hz); 8.21 (d, 1H, ArH J 8 Hz); 8.77 (m, 1H, ArH).
MS EI 70 eV (m / z,% intensity): 363 (M, 75 ~);
348 (lGO); 330 (44); 304 (33).
MSHR EI 70 eV: Mtr = 363.2195 for C29H29NO2 M ~ h =
363 ~ 21C ~ 8.
HPLC Column Waters HR C18, 8 x 100 mm, 6 ~, Waters 486 UV detector at 260 nm, flow rate 3 ml / min, eluent MeOH: H2O = 85: 15 + 0.1% TFA, acid (CB71329) tr =
4.67 mi.n 97.8%.

Claims (11)

1) Polycyclic aromatic derivatives of type retinoid of general formula:

in which the R3 and R4 groups carried by the double bond between carbons 11 and 12 are cis and R1, R2, R3, R4, R5, R6, R7, X1, X2 and X3 have the meanings following:
- R1 represents a hydrogen atom, a radical C1-C6 alkyl, or a group of the formula -CH2OH, -OH, -CHO
-COOH, -COR8, -CH2OCOR9, -SH, -S-alkyl, -PO3H2, p-hydroxyphenylaminocarbonyl, tetrazol-5-ylaminocarbonyl, tetrazol-5-yl, 5-trifluoromethyl-tetrazoyl, and when this is possible their salts with acids tolerated physiologically, where R8 and R9 are:
. a hydrogen atom, an -OH group, a radical C1-C6 alkyl or a group of formula -OR10, where R10 represents a branched or unbranched alkyl radical having from 1 to 20 carbon atoms, a branched or unbranched alkenyl radical having from 2 to 20 carbon atoms, an aryl or aralkyl radical, Where . an amino group of formula:

, in which r and r', identical or different, represent a hydrogen atom, an alkyl radical in C1-C6, an aryl or aralkyl radical, an .alpha.-amino acid residue, a sugar residue or a heterocycle in which r and r' taken together form a heterocycle.
- R2 represents a hydrogen atom, an atom of halogen and more particularly a fluorine atom, a C1-C6 alkyl radical, a group of formula -COOH, -OR11, -SR11, -(CF2)nCF3 where n is an integer between 0 and 10, or a -OCOR11 group, and when possible their salts with physiologically tolerated acids, or a amino group of formula:
, in which r and r' have the same meaning than previously, and R11 represents a hydrogen atom, a C1-C6 alkyl radical, a fluoroalkyl radical having 1 to 6 carbon atoms and 3 to 7 fluorine atoms, a aryl radical or an aralkyl radical.
- R3 represents a hydrogen atom, a radical trifluoromethyl, an aryl radical, an aralkyl radical or a C1-C6 alkyl radical optionally substituted by a hydroxyl or by one or more fluorine atoms, by a C1-C6 alkoxy or by a group of formula -(C=O)R12, in wherein R12 represents a hydrogen atom, a radical C1-C6 alkyl, a hydroxyl radical, an alkoxy radical in C1-C6 or an amino group of formula:

, in which r and r' have the same meaning than previously.
- R4 represents a hydrogen atom or a aryl radical.
- R5 represents a hydrogen atom, a radical C1-C6 alkyl, a halogen atom, a radical fluoroalkyl having 1 to 6 carbon atoms and 3 to 7 fluorine atoms, or a group of formula -OR13 where R13 represents a hydrogen atom, a C1-C6 alkyl radical, an aryl radical or an aralkyl radical or a group trifluoromethyl.
- X1 is chosen from a carbon atom, a oxygen atom or a sulfur atom, and then, - R6 and R7 are:
. methyl or ethyl radicals, in the case where X1 is a carbon atom, . nothing in the case where X1 is a sulfur atom or an oxygen atom, . one or two oxygen atoms in the case where X1 is a sulfur atom (case of a sulfoxide -SO- or a sulfone -SO2-)-- X2 and X3, identical or different, represent a carbon atom, an oxygen atom or a nitrogen atom, or alternatively X2-X3 are a single atom of sulfur, oxygen, or nitrogen, thus the nucleus carrying X2 and X3 can be benzene, pyridine, thiophene, furanic, pyrrolic, or, in the case where X2 is an atom of oxygen and X3 a carbon atom, C13 and C14 represents one and the same carbon atom, thus the nucleus carrying X2 and X3 can be isoxazole. 2) Derivatives according to claim 1, characterized in that in formula (I), R4 represents an atom of hydrogen. 3) Derivatives according to claims 1 or 2, characterized in that in formula (I), R3 represents a C1-C6 alkyl or a trifluoromethyl radical or a group -(CH2)nCF3 where n is an integer between 0 and 10. 4) Derivatives according to any of the claims 1 to 3, characterized in that in the formula (I), R2 represents a hydrogen atom and R1 represents a tetrazoyl group or a -COOH group.

5) Derivatives according to any of the claims 1 to 4:
- Acid (z) 2-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]pyridinyl-5-carboxylic.
- Acid (E) 4-[1-trifluoromethyl-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-ethenyl]benzoic acid.
- Acid (Z) 4-[1-(5,6,7,8-tetrahydro-3,5,5, 8,8-pentamethyl-2-naphthalenyl)-2-propenyl]benzoic acid.
- Acid (E) 4-[1-trifluoromethyl-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-ethenyl]benzoic acid.
- Acid (Z) 4-[1-(3',4'-dihydro-4',4'-dimethyl-1',1'-dioxide-2'H-1'-benzothiopyran-6'-yl)-2-propenyl]benzoic acid.
- (Z)-5-[4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]phenyl]-1H-tetrazole.
- Acid (E) 5-[4-[1-trifluoromethyl-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-ethenyl]phenyl]-1H-tetrazole.
- (Z) 5-[4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-propenyl]phenyl]-1H-tetrazole.
- Acid (E) 5-[4-[1-trifluoromethyl-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-ethenyl]phenyl]-1H-tetrazole.
- (Z) 5 [4-[1-(3',4'-dihydro-4',4'-dimethyl-1',1'-dioxide-2'H-1'-benzothiopyran-6'-yl)-2-propenyl]phenyl]-1H-tetrazole.
- Acid (Z) 2-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]thienyl-5-carboxylic.
- (Z) 5-[2-[1-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl)]5-thienyl]-1H
tetrazole.

-The acid (Z) 5-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]pyridinyl-2-carboxylic.
- (Z) 2-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-propenyl]pyridinyl- 5-carboxylic.
- Acid (Z) 5-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-propenyl]pyridinyl-2-carboxylic.
- Acid (Z) 5-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl)]isoxazole-3-carboxylic.
- Acid (Z) 5-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-propenyl)]isoxazole-3-carboxylic.
- (Z) 1-[4-[1-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]phenyl]-5-trifluoromethyl-1H-tetrazole. 6) Therapeutic, dermatological or cosmetic containing at least one derivative of formula (I) defined in any one of claims 1 to 5, under free form or in the form of a pharmaceutically salt acceptable, in combination with a vehicle or diluent traditional. 7) Use of a derivative of formula (I) defined in any one of claims 1 to 5, for the manufacture of a therapeutic composition useful in the treatment or prevention of cancer. 8) Use of a derivative of formula (I) defined in any one of claims 1 to 5, for the manufacture of a therapeutic composition useful in the treatment or prevention of non-insulin-dependent diabetes. 9) Use of a derivative of formula (I) defined in any one of claims 1 to 5, for the manufacture of a therapeutic composition useful in the treatment or prevention of inflammatory diseases. 10) Use of a derivative of formula (I) defined in any one of claims 1 to 5, for the manufacture of a therapeutic composition useful in the treatment or prevention of immune diseases. 11) Use of a derivative of formula (I) defined in any one of claims 1 to 5, for the manufacture of a dermatological or cosmetic composition useful in the treatment or prevention of diseases of the skin.